1. health and fitness
2. disease

The Endocrine Society’s
CLINICAL
GUIDELINES
Case Detection, Diagnosis,
and Treatment of Patients
with Primar y Aldosteronism:
An Endocrine Society Clinical Practice Guideline
The Endocrine Society
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815
301.941.0200
www.endo-society.org
Authors: John W. Funder, Robert M. Carey, Carlos Fardella, Celso E. Gomez-Sanchez, Franco Mantero, Michael
Stowasser, William F. Young Jr.,
Jr, and
andVictor
VictorM.
M.Montori
Montori
Affiliations: Prince Henry's
Henry’s Institute of Medical Research (J.W.F.), Clayton; Australia; University of Virginia
Health System (R.M.C.), Charlottesville, Virginia; Facultad de Medicina Pontificia Universidad Católica de
Chile (C.F.), Santiago; Chile; G.V. (Sonny) Montgomery VA Medical Center (C.E.G-S.), Jackson, Mississippi;
University of Padova (F.M.), Padua; Italy; University
University of
of Queensland
Queensland (M.S.),
(M.S.), Brisbane;
Brisbane; Australia;
Australia and Mayo Clinic
(W.F.Y., V.M.M.), Rochester, Minnesota.
Co-Sponsoring Associations: European Society of Endocrinology, European Society of Hypertension,
International Society of Endocrinology, International Society of Hypertension, The Japanese Society of
Hypertension
Disclaimer Statement: Clinical Practice Guidelines are developed to be of assistance to endocrinologists by
providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered
inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific
outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a
particular patient. Treatment decisions must be made based on the independent judgment of health care providers
and each patient's individual circumstances.
The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifically
excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be
liable for direct, indirect, special, incidental, or consequential damages related to the use of the information
contained herein.
First published in the Journal of Clinical Endocrinology & Metabolism, September 2008, 93(9):
3266–3281
© The Endocrine Society, 2008
The Endocrine Society’s
CLINICAL
GUIDELINES
Case Detection, Diagnosis,
and Treatment of Patients
with Primar y Aldosteronism:
An Endocrine Society Clinical Practice Guideline
Table of Contents
Summary of Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Methods of Development of Evidence-Based Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Definition and Clinical Significance of Primary Aldosteronism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Case Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Case Confirmation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Subtype Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Order Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Reprint Information, Questions & Correspondences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Back Cover
Abstract
Conclusions: We recommend case detection of
the diagnosis and treatment of patients with primary
aldosteronism.
primary aldosteronism be sought in higher risk groups
of hypertensive patients and those with hypokalemia
by determining the aldosterone-renin ratio under
standard conditions, and that the condition be
confirmed/excluded by one of four commonly used
confirmatory tests. We recommend that all patients
with primary aldosteronism undergo adrenal
computed tomography (CT) as the initial study in
subtype testing and to exclude adrenocortical
carcinoma. We recommend the presence of a
unilateral form of primary aldosteronism should be
established/excluded by bilateral adrenal venous
sampling by an experienced radiologist and,
where present, optimally treated by laparoscopic
adrenalectomy. We recommend that patients with
bilateral adrenal hyperplasia, or those unsuitable
for surgery, optimally be treated medically by
mineralocorticoid receptor antagonists.
Participants: The Task Force comprised a chair,
selected by the Clinical Guidelines Subcommittee
(CGS) of The Endocrine Society, six additional
experts, one methodologist, and a medical writer. The
Task Force received no corporate funding or
remuneration.
Evidence: Systematic reviews of available evidence
were used to formulate the key treatment and
prevention recommendations. We used the Grading
of Recommendations, Assessment, Development,
and Evaluation (GRADE) group criteria to describe
both the quality of evidence and the strength
of recommendations. We used ‘recommend’ for
strong recommendations and ‘suggest’ for weak
recommendations.
(J Clin Endocrinol Metab 93: 3266–3281, 2008)
Consensus
Process: Consensus was guided by
systematic reviews of evidence and discussions during
one group meeting, several conference calls, and
multiple e-mail communications. The drafts prepared
by the task force with the help of a medical writer
were reviewed successively by The Endocrine
Society’s CGS, Clinical Affairs Core Committee
(CACC), and Council. The version approved by the
CGS and CACC was placed on The Endocrine
Society's Web site for comments by members. At
each stage of review, the Task Force received written
comments and incorporated needed changes.
Abbreviations:
APA, aldosterone-producing adenoma; ARR, plasma aldosterone: renin ratio;
AVS, adrenal venous sampling; CT, computed tomography; DRC, direct rennin
concentration; FST, fludrocortisone suppression testing; GRA,
glucocorticoidremediable aldosteronism; IHA, idiopathic hyperaldosteronism;
MR, mineralocorticoid receptor; MRI, magnetic resonance imaging; PA,
primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma
rennin activity; SIT, saline infusion test; UAH, unilateral adrenal hyperplasia
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Objective: To develop clinical practice guidelines for
3
SUMMARY OF
RECOMMENDATIONS
1.0.CASE DETECTION
1.1. We recommend the case detection of primary
aldosteronism (PA) in patient groups with relatively
high prevalence of PA. (1|
) These include
patients with Joint National Commission (JNC)
stage 2 (>160–179/100–109 mm Hg), stage 3
(>180/110 mm Hg), or drug resistant hypertension;
hypertension and spontaneous or diuretic-induced
hypokalemia; hypertension with adrenal incidentaloma; or hypertension and a family history of earlyonset hypertension or cerebrovascular accident at a
young age (<40 years). We also recommend case
detection for all hypertensive first-degree relatives of
patients with PA. (1|
)
1.2. We recommend use of the plasma aldosterone-
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
3.3. In patients with onset of confirmed PA earlier
than at 20 years of age and in those who have a family
history of PA or of strokes at young age (<40 years),
we suggest genetic testing for glucocorticoidremediable aldosteronism (GRA). (2|
)
4.0.TREATMENT
4.1. We recommend that treatment by unilateral
laparoscopic adrenalectomy be offered to patients with
documented unilateral PA (i.e., aldosterone-producing
adenoma [APA] or unilateral adrenal hyperplasia
[UAH]). (1|
) If a patient is unable or
unwilling to undergo surgery, we recommend medical
treatment with a mineralocorticoid receptor (MR)
antagonist. (1|
)
renin ratio (ARR) to detect cases of PA in these
patient groups. (1|
)
4.2. In patients with PA due to bilateral adrenal
2.0.CASE CONFIRMATION
disease, we recommend medical treatment with an MR
antagonist (1|
); we suggest spironolactone
as the primary agent with eplerenone as an alternative.
(2|
)
2.1. Instead of proceeding directly to subtype
classification, we recommend that patients with a
positive aldosterone-renin ratio (ARR) undergo
testing, by any of four confirmatory tests, to
definitively confirm or exclude the diagnosis.
(1|
)
4
3.2. We recommend that, when surgical treatment is
practicable and desired by the patient, the distinction
between unilateral and bilateral adrenal disease be
made by adrenal venous sampling (AVS) by an
experienced radiologist. (1|
)
3.0.SUBTYPE CLASSIFICATION
3.1. We recommend that all patients with PA
undergo an adrenal computed tomography (CT) scan
as the initial study in subtype testing and to exclude
large masses that may represent adrenocortical
carcinoma. (1|
)
4.3. In patients with GRA, we recommend the use of
the lowest dose of glucocorticoid that can normalize
blood pressure and serum potassium levels rather
than first-line treatment with an MR antagonist.
(1|
)
METHOD OF DEVELOPMENT OF
EVIDENCE-BASED GUIDELINES
The Clinical Guidelines Subcommittee of The
Endocrine Society deemed detection, diagnosis, and
treatment of patients with primary aldosteronism
(PA) a priority area in need of practice guidelines and
appointed a seven-member Task Force to formulate
evidence-based recommendations. The Task Force
followed the approach recommended by the Grading
of Recommendations, Assessment, Development, and
Evaluation group, an international group with
expertise in development and implementation of
evidence-based guidelines (1).
Linked to each recommendation is a description of the
evidence, values that panelists considered in making
the recommendation (when making these explicit
was necessary), and remarks, a section in which
panelists offer technical suggestions for testing
conditions, dosing and monitoring. These technical
comments reflect the best available evidence applied
to a typical patient. Often, this evidence comes from
the unsystematic observations of the panelists and
should, therefore, be considered suggestions.
What is primary aldosteronism?
Primary aldosteronism (PA) is a group of disorders
in which aldosterone production is inappropriately
high, relatively autonomous, and non-suppressible
by sodium loading. Such inappropriate production
of aldosterone causes cardiovascular damage,
suppression of plasma renin, hypertension, sodium
retention, and potassium excretion that if prolonged
and severe may lead to hypokalemia. PA is commonly
caused by an adrenal adenoma, by unilateral or
bilateral adrenal hyperplasia, or in rare cases by the
inherited condition of glucocorticoid-remediable
aldosteronism (GRA).
How common is PA?
Most experts previously described PA in <1% of
patients with mild-to-moderate essential hypertension and had assumed hypokalemia was a sine
qua non for diagnosis (3–9). Accumulating evidence
has challenged these assumptions. Cross-sectional
and prospective studies report PA in >10% of
hypertensive patients, both in general and in specialty
settings (10–18).
How frequent is hypokalemia in PA?
In recent studies, only a minority of patients with
PA (9% to 37%) had hypokalemia (19). Thus,
normokalemic hypertension constitutes the most
common presentation of the disease, with hypokalemia probably present in only the more severe
cases. Half the patients with an aldosteroneproducing adenoma (APA) and 17% of those with
idiopathic hyperaldosteronism (IHA) had serum
potassium concentrations <3.5 mmol/L (17, 20).
Thus, the presence of hypokalemia has low sensitivity
and specificity, and a low positive predictive value for
the diagnosis of PA.
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
The Task Force used the best available research
evidence that members identified to inform the
recommendations and consistent language and
graphical descriptions of both the strength of a
recommendation and the quality of evidence. In terms
of the strength of the recommendation, strong
recommendations use the phrase “we recommend”
and the number 1, and weak recommendations use the
phrase “we suggest” and the number 2. Cross-filled
circles indicate the quality of the evidence, such that
denotes very low quality evidence;
, low quality;
, moderate quality; and
, high quality. The Task Force has confidence
that patients who receive care according to the strong
recommendations will derive, on average, more good
than harm. Weak recommendations require more
careful consideration of the patient’s circumstances,
values and preferences to determine the best course of
action. A detailed description of this grading scheme
has been published elsewhere (2).
DEFINITION AND CLINICAL
SIGNIFICANCE OF PRIMARY
ALDOSTERONISM
5
Why is PA important?
This condition is important not only because of its
prevalence, but also because PA patients have higher
cardiovascular morbidity and mortality than age- and
sex-matched patients with essential hypertension and
the same degree of blood pressure elevation (21, 22).
Furthermore, specific treatments are available that
ameliorate the impact of this condition on patientimportant outcomes.
1.0. CASE DETECTION
1.1. We recommend the case detection of primary
aldosteronism (PA) in patient groups with relatively
high prevalence of PA (listed in Table 1) (Figure 1).
(1|
) These include patients with Joint
National Commission (JNC) stage 2 (>160–179/
100–109 mm Hg), stage 3 (>180/110 mm Hg), or
drug resistant hypertension; hypertension and
spontaneous or diuretic-induced hypokalemia;
hypertension with adrenal incidentaloma; or
hypertension and a family history of early-onset
hypertension or cerebrovascular accident at a young
age (<40 years). We also recommend case detection
for all hypertensive first-degree relatives of patients
with PA. (1|
)
1.1.EVIDENCE
Indirect evidence links the detection of PA with
improved patient outcomes. There are no clinical trials
of screening that measure the impact of this practice on
morbidity, mortality, or quality of life outcomes.
Patients could potentially be harmed by the work up
and treatment (i.e., by withdrawal of antihypertensive medication, invasive vascular examination,
adrenalectomy) aimed at vascular protection along
with easier and better blood pressure control. There is
strong evidence linking improved blood pressure
control and reduction in aldosterone levels to
improved cardiac and cerebrovascular outcomes (38).
Until prospective studies inform us differently, we
recommend that all hypertensive first-degree relatives
of patients with PA undergo ARR testing.
1.1.VALUES
Our recommendation to detect cases of PA places a
high value on avoiding the risks associated with
missing the diagnosis (and thus forgoing the
opportunity of a surgical cure or improved control of
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
TABLE 1. Groups with high prevalence of primary aldosteronism
6
Patient group
Prevalence
Moderate/severe hypertension The prevalence rates cited here are
from Mosso (16). Others have reported similar estimates (18, 23–25). The
classification of blood pressure for adults (aged 18 years and older) was
based on the Sixth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC) which
establishes three different stages: Stage 1 = SBP 140-159, DBP 90-99; Stage
2 = SBP 160-179, DBP 100–109; Stage 3 = SBP >180, DBP >110 (10).
When systolic and diastolic blood pressures were in different categories, the
higher category was selected to classify the individual’s blood pressure status.
Overall: 6.1%
Stage 1 (mild): 2%
Stage 2 (moderate): 8%
Stage 3 (severe): 13%
Resistant hypertension, defined as SBP >140 and DBP >90 despite
treatment with three hypertensive medications. The prevalence rates cited
here are from (26–31).
17%–23%
Hypertensive patients with spontaneous or diureticinduced PA is hypokalemia.
Specific prevalence figures are not available,
but more frequently found in this group.
Hypertension with adrenal incidentaloma (32–37), defined as an
adrenal mass detected incidentally during imaging performed for extraadrenal reasons.
Median: 2% (range, 1.1%–10%)
One retrospective study that excluded patients
with hypokalemia and severe hypertension
found aldosterone-producing adenoma in 16
of 1004 subjects (37).
Primary Aldosteronism
Patients with hypertension that are at increased risk for PA
_
PA unlikely
Use ARR to detect cases 1|
+
_
PA unlikely
Conduct confirmatory testing 1|
+
Adrenal CT (1|
}
If surgery desired
If surgery not desired
AVS (1|
Bilateral
Treat with MR antagonist (1|
)
)
}
Subtype testing*
Unilateral
Treat with laparoscopic adrenalectomy (1|
)
*In patients with confirmed PA who have a family history of PA or of strokes at young age (<40 years), or with onset of hypertension
earlier than at 20 years of age, we suggest genetic testing for glucocorticoid-remediable aldosteronism (GRA) (2|
). In patients
with GRA, we recommend the use of the lowest dose of glucocorticoid receptor (GR) agonist that can normalize blood pressure and
serum potassium levels (1|
).
hypertension through specific medical treatment) and
a lower value on avoiding the risk of falsely classifying
a hypertensive patient as having PA and exposing
him or her to additional diagnostic testing.
1.2. We recommend use of the plasma aldosterone-
renin ratio (ARR) to detect cases of PA in these
patient groups (Figure 1). (1|
)
1.2.EVIDENCE
The ARR is currently the most reliable available
means of screening for PA. Although valid estimates
of test characteristics of the ARR are lacking (mainly
due to limitations in the design of studies that have
addressed this issue) (39), numerous studies have
demonstrated the ARR to be superior to
measurement of potassium or aldosterone (both of
which have lower sensitivity) or of renin (which is
less specific) in isolation (40–42).
Like all biochemical case detection tests, the ARR is
not without false positives and negatives (17, 18, 39,
43–45). Table 2 documents the effect of medications
and conditions on the ARR. The ARR should
therefore be regarded as a detection test only, and
should be repeated if the initial results are
inconclusive or difficult to interpret because of
suboptimal sampling conditions (e.g., maintenance of
some medications listed in Table 2).
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Figure 1. Algorithm for the detection, confirmation, subtype testing, and treatment of primary aldosteronism (PA). We recommend the
case detection of PA in patient groups with relatively high prevalence of PA (1|
)—these include patients with moderate, severe,
or resistant hypertension, spontaneous or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, or a family history of
early onset hypertension or cerebrovascular accident at a young age (<40 years). We recommend use of the plasma aldosterone:renin
ratio (ARR) to detect cases of PA in these patient groups (1|
). We recommend that patients with a positive ARR undergo testing,
using any of four confirmatory tests, to definitively confirm or exclude the diagnosis (1|
). We recommend that, all patients with
PA undergo an adrenal CT scan as the initial study in subtype testing and to exclude adrenocortical carcinoma (1|
). When
surgical treatment is practicable and desired by the patient, the distinction between unilateral and bilateral adrenal disease should be
made by adrenal venous sampling (AVS) (1|
). We recommend that treatment by unilateral laparoscopic adrenalectomy be
offered to patients with AVS-documented unilateral aldosterone-producing adenoma (1|
). If a patient is unable or unwilling to
undergo surgery, we recommend medical treatment with an mineralocorticoid receptor (MR) antagonist (1|
) In patients with PA
due to bilateral adrenal disease, we recommend medical treatment with an MR antagonist (1|
).
7
1.2.VALUES
Similar values underpin our recommendation to
target subjects in groups with documented high
prevalence of PA and to test them by ARR. In
particular, this recommendation acknowledges the
costs currently associated with ARR testing of all
patients with essential hypertension. Against this
recommendation for selective testing, however,
must be weighed the risk of missing or at least
delaying the diagnosis of PA in some hypertensive
individuals. The consequences of this may include
the later development of more severe and resistant
hypertension resulting from failure to lower levels of
aldosterone or to block its actions. Furthermore,
duration of hypertension has been reported by several
investigators to be a negative predictor of outcome
following unilateral adrenalectomy for aldosteroneproducing adenoma (46, 47), suggesting that delays in
diagnosis may result in a poorer response to specific
treatment once PA is finally diagnosed.
1.2. Remarks—technical aspects required for the
correct implementation of recommendation 1.2.
Testing conditions (Table 3 & 4)
The ARR is most sensitive when used in patients from
whom samples are collected in the morning after patients
have been out of bed for at least 2 hours, usually after
they have been seated for 5–15 minutes. Ideally, patients
should have unrestricted dietary salt intake prior to
testing. In many cases the ARR can be confidently
interpreted with knowledge of the effect on the ARR of
continued medications or suboptimal conditions of
testing, avoiding delay and allowing the patient to
proceed directly to confirmatory/exclusion testing.
Washout of all interfering antihypertensive medications
is feasible in patients with mild hypertension, but is
potentially problematic in others, and perhaps
unnecessary in that medications with minimal effect on
the ARR can be used in their place (Table 2).
Assay reliability
Although newer techniques are evolving, we prefer to
use validated immunometric assays for plasma renin
activity (PRA) or direct renin concentration (DRC);
PRA takes into account factors (such as estrogencontaining preparations) that affect endogenous
substrate levels. Laboratories should use aliquots from
human plasma pools, carefully selected to cover the
critical range of measurements, rather than the
lyophilized controls provided by the manufacturer to
monitor intra- and inter-assay reproducibility and longterm stability. Because the ARR is mathematically
highly dependent on renin (49), renin assays should be
sufficiently sensitive to measure levels as low as 0.2–0.3
ng/mL/h (DRC 2 mU/L) (10, 16). For PRA, but not
DRC, sensitivity for levels <1 ng/mL/h can be
improved by prolonging the duration of the assay
TABLE 2. Medications that have minimal effects on plasma aldosterone levels and can be used to
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
control hypertension during case finding and confirmatory testing for primary aldosteronism
8
Drug
Class
Usual dose
Comments
Verapamil
slow-release
Non-dihydropyridine
antagonist calcium
channel
90–120 mg twice daily
Use singly or in combination with the other agents
listed in this Table.
Hydralazine
Vasodilator
10–12.5 mg twice daily, Commence verapamil slow-release first to
increasing as required prevent reflex tachycardia. Commencement at low
doses reduces risk of side effects (including
headaches, flushing, and palpitations).
Prazosin
hydrochloride
Alpha-adrenergic
blocker
0.5–1 mg two to three
times daily, increasing
required
Monitor for postural hypotension.
Doxazosin mesylate
Alpha-adrenergic
blocker
1–2 mg once daily,
increasing as required
Monitor for postural hypotension.
Terazosin
hydrochloride
Alpha-adrenergic
blocker
1–2 mg once daily,
increasing as required
Monitor for postural hypotension.
TABLE 3. Measurement of the aldosterone-renin ratio: a suggested approach
A. Preparation for aldosterone-renin ratio (ARR) measurement: agenda
1. Attempt to correct hypokalemia, after measuring plasma potassium in blood collected slowly with a syringe and
needle [preferably not a Vacutainer to minimize the risk of spuriously raising potassium], avoiding fist clenching
during collection, waiting at least 5 seconds after tourniquet release (if used) to achieve insertion of needle, and
ensuring separation of plasma from cells within 30 minutes of collection.
2. Encourage patient to liberalize (rather than restrict) sodium intake.
3. Withdraw agents that markedly affect the ARR (48) for at least 4 weeks:
a. Spironolactone, eplerenone, amiloride, and triamterene
b. Potassium-wasting diuretics
c. Products derived from liquorice root (e.g., confectionary licorice, chewing tobacco)
4. If the results of ARR off the above agents are not diagnostic, and if hypertension can be controlled with relatively noninterfering medications (see Table 2), withdraw other medications that may affect the ARR (48) for at least 2 weeks:
a. Beta-adrenergic blockers, central alpha-2 agonists (e.g., clonidine, alpha-methyldopa), nonsteroidal antiinflammatory drugs
b. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, dihydropyridine calcium
channel antagonists
5. If necessary to maintain hypertension control, commence other antihypertensive medications that have lesser effects
on the ARR (e.g., verapamil slow-release, hydralazine [with verapamil slow-release, to avoid reflex tachycardia],
prazosin, doxazosin, terazosin; see Table 2).
6. Establish oral contraceptive (OC) and hormone replacement therapy (HRT) status, as estrogen-containing medications
may lower direct renin concentration (DRC) and cause false positive ARR when DRC (rather than plasma renin
activity) is measured. Do not withdraw OC unless confident of alternative effective contraception.
B. Conditions for collection of blood
2. Collect blood carefully, avoiding stasis and hemolysis (see A.1 above).
3. Maintain sample at room temperature (and not on ice, as this will promote conversion of inactive to active renin)
during delivery to laboratory and prior to centrifugation and rapid freezing of plasma component pending assay.
C. Factors to take into account when interpreting results (see Table 4)
1. Age: in patients aged >65 years, renin can be lowered more than aldosterone by age alone, leading to a raised ARR
2. Time of day, recent diet, posture, and length of time in that posture
3
Medications
4. Method of blood collection, including any difficulty doing so
5. Level of potassium
6. Level of creatinine (renal failure can lead to false positive ARR)
incubation phase as suggested by Sealey and Laragh
(50). Although most laboratories use radioimmunoassay for plasma and urinary aldosterone,
measured levels of standards have been shown to be
unacceptably different in some instances (51). Tandem
mass spectrometry is increasingly used and has proved
to be much more consistent in performance (52).
Interpretation
There are important and confusing differences
between laboratories in the methods and units
used to report values of renin and aldosterone. For
aldosterone, 1 ng/dL converts to 27.7 pmol/L in
Système International [SI] units. For immunometric
methods of directly measuring renin concentration,
a PRA level of 1 ng/mL/h (12.8 pmol/L/min
in SI units) converts to a DRC of approximately
8.2 mU/L (5.2 ng/L in traditional units) when
measured by either the Nichols Institute Diagnostics
automated chemiluminescence immunoassay (previously
widely used but recently withdrawn) or the Bio-Rad
Renin II radioimmunoassay. Because DRC assays are
still in evolution, these conversion factors may
change. For example, 1 ng/mL/h PRA converts to a
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
1. Collect blood mid-morning, after the patient has been up (sitting, standing, or walking) for at least 2 hours and
seated for 5-15 minutes.
9
TABLE 4. Factors that may affect the aldosterone-renin ratio and thus lead to false positive or false
negative results
Effect on
renin levels
Effect on
ARR
↑
↑ ↑
↑ (FP)
↑
↑ ↑
↑ (FP)
↑
Factor
Effect on
aldosterone
levels
Medications
Central alpha-2 agonists
(e.g., clonidine, alpha-methyldopa
NSAIDs
↑ ↑
Beta-adrenergic blockers
↑ (FP)
↑ ↑
↑
K+-sparing diuretics
↑
↑ ↑
↑
(FN)
ACE inhibitors
↑
↑ ↑
↑
(FN)
ARBs
↑
↑ ↑
↑
(FN)
↑
↑
(FN)
↑
↑
↑
↑ *
↑ (FP)*
↑
(FN)*
↑
↑
↑
(FN)
↑
↑
↑
Renin inhibitors
↑
Ca2+ blockers (DHPs)
↑
(FN)
K+-wasting diuretics
↑ (FP)
Potassium status
Hypokalemia
↑
Potassium loading
↑
Dietary sodium
↑
↑ (FP)
(FN)
↑
↑ ↑
↑ (FP)
↑
↑
↑ (FP)
↑
↑
Advancing age
↑ ↑
↑ ↑
Sodium loaded
↑
↑
Sodium restricted
↑ (FP)
↑
↑ ↑
Other conditions
Renal impairment
(FN)
Renovascular HT
↑
↑ ↑
↑
(FN)
Malignant HT
↑
↑ ↑
↑
10
Pregnancy
↑
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
PHA-2
(FN)
ARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K+, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1
receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2 (familial hypertension and hyperkalemia with normal glomerular filtration
rate); HT, hypertension; FP, false positive; FN, false negative.
*Renin inhibitors lower plasma renin activity (PRA), but raise direct active renin concentrations (DRC). This would be expected to result in false positive ARR
levels for renin measured as PRA and false negatives for renin measured as DRC.
DRC of approximately 12 mU/L (7.6 ng/L) when
measured by the recently introduced and already
widely used Diasorin automated chemiluminescence
immunoassay. Here, we express aldosterone and
PRA levels in conventional units (aldosterone in
nanograms per deciliter; plasma renin activity in
nanograms per milliliter per hour) with SI units for
aldosterone and DRC (using the 8.2 conversion
factor) given in parentheses. Lack of uniformity in
diagnostic protocols and assay methods for ARR
measurement has been associated with substantial
variability in cut-off values used by different groups
ranging from 20 to 100 (68 to 338) (11, 14, 15, 19, 29,
53, 54). Most groups, however, use cut-offs of 20 to 40
(68 to 135) when testing is performed in the morning
on a seated ambulatory patient. Table 5 lists ARR cutoff values using some commonly expressed assay units
for plasma aldosterone concentration, plasma renin
activity, and direct measurement of plasma renin
concentration.
prudent to point out relative advantages and
disadvantages, leaving clinicians the flexibility to
judge for themselves.
Some investigators require elevated aldosterone levels
in addition to elevated ARR for a positive screening
test for PA (usually aldosterone >15 ng/dL [416
pmol/L]) (55). An alternative approach is to avoid a
formal cut-off level for plasma aldosterone, but to
recognize that the likelihood of a false positive ARR
becomes greater when renin levels are very low (11).
Against a formal cut-off level for aldosterone are the
findings of several studies. In one study, seated
plasma aldosterone levels were <15 ng/dL (<416
pmol/L) in 36% of 74 patients diagnosed with PA
after screening positive by ARR defined as >30
(>100) and showing failure of aldosterone to suppress
during fludrocortisone suppression testing (FST), and
in four of 21 patients found by adrenal venous
sampling (AVS) to have unilateral, surgically
correctable PA (56). Another study reported plasma
aldosterone levels of 9–16 ng/dL (250–440 pmol/L) in
16 of 37 patients diagnosed with PA by FST (16).
While it would clearly be desirable to provide firm
recommendations for ARR and plasma aldosterone
cut-offs, the variability of assays between laboratories
and the divided literature to date make it more
2.1. Instead of proceeding directly to subtype
classification, we recommend that patients with a
positive ARR measurement undergo testing, by any of
four confirmatory tests, to definitively confirm or
exclude the diagnosis (Figure 1). (1|
)
2.0. CASE CONFIRMATION
2.1.EVIDENCE
The current literature does not identify a gold standard
confirmatory test for PA. Test performance has been
evaluated only retrospectively, in relatively small series
of patients selected with high prior (pre-test)
probability of PA, commonly in comparison with other
tests rather than towards a conclusive diagnosis of PA.
TABLE 5. ARR cut-off values, depending on assay and based on whether PAC, PRA, and DRC are
measured in conventional or SI units
PRA
(measured in
ng/mL/h)
PAC (as ng/dL)
PAC (as pmol/L)
PRA
(measured in
pmol/L/min)
DRCa
(measured in
mU/L)
DRCa
(measured in
ng/L)
20
30b
40
1.6
2.5
3.1
2.4
3.7
4.9
3.8
5.7
7.7
750b
1000
60
80
91
122
144
192
ARR, Aldosterone-renin ratio; PAC, plasma aldosterone concentration; PRA, plasma renin activity; DRC, direct renin concentration; SI, Système International.
a Values shown are on the basis of a conversion factor of PRA (ng/mL/h) to DRC (mU/L) of 8.2. DRC assays are still in evolution, and in a recently introduced
and already commonly used automated DRC assay, the conversion factor is 12 (see text).
b The most commonly adopted cut-off values are shown in bold: 30 for PAC and PRA in conventional units (equivalent to 830 when PAC is in SI units) and 750
when PAC is expressed in SI units (equivalent to 27 in conventional units).
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Some of these limitations are illustrated in the
following example. There is empirical evidence that
case-control designs for establishing the accuracy of
diagnostic tests overestimate their accuracy.
Giacchetti et al. (57) used such a design including 61
PA patients (26 with confirmed APA) and 157
patients with essential hypertension. In this context,
they found that a post-sodium infusion test with a
cut-off value for plasma aldosterone of ≥ 7 ng/dL
11
showed a sensitivity of 88% and a specificity of 100%
when evaluated by ROC curve in the 76 cases with
ARR >40 ng/dL per ng/mL/h. In the prospective
PAPY study, analysis of sensitivity/specificity in the
317 patients undergoing a saline infusion test (SIT)
gave a best aldosterone cut-off value of 6.8 ng/dL. The
sensitivity and specificity, however, were moderate
(respectively 83% and 75%), reflecting values
overlapping between patients with and without
disease; use of the aldosterone-cortisol ratio did not
improve the accuracy of the test (17, 58).
Four testing procedures (oral sodium loading, saline
infusion, fludrocortisone suppression, and captopril
challenge) are in common use, and there is currently
insufficient direct evidence to recommend one over
the others. While it is acknowledged that these tests
may differ in terms of sensitivity, specificity, and
reliability, the choice of confirmatory test is
commonly determined by considerations of cost,
patient compliance, laboratory routine, and local
expertise (Table 6). It should be noted that
confirmatory tests requiring oral or intravenous
sodium loading should be administered with caution
in patients with uncontrolled hypertension or
congestive heart failure. We recommend that the
pharmacological agents with minimal or no effects on
the renin-angiotensin-aldosterone system shown in
Table 2 be utilized to control blood pressure during
confirmatory testing.
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
2.1.VALUES
12
Confirmatory testing places a high value on sparing
individuals with false-positive ARR tests costly and
intrusive lateralization procedures.
2.1.REMARKS
For each of the four confirmatory tests, procedures,
interpretations, and concerns are described in Table 6.
3.0. SUBTYPE CLASSIFICATION
3.1. We recommend that all patients with PA
undergo an adrenal computed tomography (CT) scan
as the initial study in subtype testing and to exclude
large masses that may represent adrenocortical
carcinoma (Figure 1). (1|
)
3.1.EVIDENCE
The findings on adrenal CT—normal-appearing
adrenals, unilateral macroadenoma (>1 cm), minimal
unilateral adrenal limb thickening, unilateral
microadenomas (≤1 cm), or bilateral macro- or microadenomas (or a combination of the two)—are used in
conjunction with AVS and, if needed, ancillary tests
to guide treatment decisions in patients with PA.
APA may be visualized as small hypodense nodules
(usually <2 cm in diameter) on CT. IHA adrenal
glands may be normal on CT or show nodular
changes. Aldosterone-producing adrenal carcinomas
are almost always >4 cm in diameter, but occasionally
smaller, and like most adrenocortical carcinomas have
a suspicious imaging phenotype on CT (69).
Adrenal CT has several limitations. Small APAs may
be interpreted incorrectly by the radiologist as “IHA”
on the basis of CT findings of bilateral nodularity or
normal-appearing adrenals. Moreover, apparent
adrenal microadenomas may actually represent areas
of hyperplasia, and unilateral adrenalectomy would be
inappropriate. In addition, nonfunctioning unilateral
adrenal macroadenomas are not uncommon,
especially in older patients (>40 years) (70) and are
indistinguishable from APAs on CT. Unilateral UAH
may be visible on CT or the UAH adrenal may appear
normal on CT.
In one study, CT contributed to lateralization in only
59 of 111 patients with surgically proven APA; CT
detected fewer than 25% of the APAs that were
smaller than 1 cm in diameter (62). In another study
of 203 patients with PA who were evaluated with both
CT and AVS, CT was accurate in only 53% of patients
(71). On the basis of CT findings, 42 patients (22%)
would have been incorrectly excluded as candidates
TABLE 6. Primary aldosteronism confirmatory tests
Confirmatory
test
Interpretation
Oral sodium
loading test
Patients should increase their
sodium intake to >200 mmol (~6
g) per day for 3 days, verified by
24-hour urine sodium content.
Patients should receive adequate
slow-release potassium chloride
supplementation to maintain
plasma potassium in the normal
range. Urinary aldosterone is
measured in the 24-hour urine
collection from the morning of day
3 to the morning of day 4.
PA is unlikely if urinary
aldosterone is lower
than 10 mcg/24-hr
(27.7 nmol/day) in the
absence of renal disease
where PA may co-exist
with lower measured
urinary aldosterone
levels. Elevated urinary
aldosterone excretion
(>12 mcg/24-hr
[>33.3 nmol/d] at the
Mayo Clinic, >14 mcg/
24-hr (38.8 nmol/d) at
the Cleveland Clinic)
makes PA highly likely.
This test should not be performed in patients
with severe uncontrolled hypertension, renal
insufficiency, cardiac insufficiency, cardiac
arrhythmia, or severe hypokalemia. 24-hour
urine collection may be inconvenient.
Laboratory-specific poor performance of the
radio-immunoassay for urinary aldosterone
(aldosterone 18-oxo-glucuronide or acidlabile metabolite) may blunt diagnostic
accuracy—a problem obviated by the
currently available HPLC-tandem mass
spectrometry methodology (52). Aldosterone
18-oxo-glucuronide is a renal metabolite, and
its excretion may not rise in patients with renal
disease.
Saline
infusion test
Patients stay in the recumbent
position for at least 1 hour before
and during the infusion of 2 liters
of 0.9% saline i.v. over 4 hours,
starting at 8:00–9.30 a.m. Blood
samples for renin, aldosterone,
cortisol, and plasma potassium
are drawn at time zero and after
4 hours, with blood pressure and
heart rate monitored throughout
the test.
Post-infusion plasma
aldosterone levels <5
ng/dL make the
diagnosis of PA unlikely,
and levels >10 ng/dL
are a very probable sign
of PA. Values between 5
and 10 ng/dL are
indeterminate (57-60).
This test should not be performed in patients
with severe uncontrolled hypertension, renal
insufficiency, cardiac insufficiency, cardiac
arrhythmia, or severe hypokalemia.
Fludrocortisone
suppression test
Patients receive 0.1 mg oral
fludrocortisone every 6 hours for
4 days, together with slow-release
KCI supplements (every 6 hours at
doses sufficient to keep plasma
K+, measured 4 times a day, close
to 4.0 mmol/L), slow-release NaCl
supplements (30 mmol three times
daily with meals) and sufficient
dietary salt to maintain a urinary
sodium excretion rate of at least 3
mmol/kg body weight. On day 4,
plasma aldosterone and PRA are
measured at 10 a.m. with the
patient in the seated posture, and
plasma cortisol is measured at 7
a.m. and 10 a.m.
Upright plasma
aldosterone >6 ng/dL on
day 4 at 10 a.m.
confirms PA, provided
PRA is <1 ng/mL/h and
plasma cortisol
concentration is lower
than the value obtained
at 7 a.m. (to exclude a
confounding ACTH
effect) (42, 43, 56, 6163).
While some centers (10, 16) conduct this test
in the outpatient setting (provided that patients
are able to attend frequently to monitor their
potassium), in other centers several days of
hospitalization are customary.
Patients receive 25–50 mg of
captopril orally after sitting or
standing for at least 1 hour. Blood
samples are drawn for
measurement of PRA, plasma
aldosterone, and cortisol at time
zero and at 1 or 2 hours after
challenge, with the patient
remaining seated during this
period.
Plasma aldosterone is
normally suppressed by
captopril (>30%). In
patients with PA it
remains elevated and
PRA remains suppressed.
Differences may be seen
between patients with
APA and those with IHA,
in that some decrease of
aldosterone levels is
occasionally seen in IHA
(23, 64–66).
There are reports of a substantial number of
false negative or equivocal results (67, 68).
Captopril
challenge test
Concerns
Most of the data available come from the
Brisbane group (42, 43, 56, 61-63) who have
established, on the basis of a very large series
of patients, a cut-off of a plasma aldosterone
concentration of 6 ng/dL at 10 a.m. in an
ambulatory patient on day 4.
Proponents of the FST argue that (1) it is the
most sensitive for confirming PA, (2) it is a less
intrusive method of sodium loading than SIT
and therefore less likely to provoke non-renindependent alterations of aldosterone levels, (3)
it allows for the potentially confounding effects
of potassium to be controlled, and for ACTH
(via cortisol) to be monitored and detected,
and (4) it is safe when performed by
experienced hands.
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Procedure
13
for adrenalectomy, and 48 (25%) might have had
unnecessary or inappropriate surgery (71). In a recent
study, AVS was performed in 41 patients with PA, and
concordance between CT and AVS was only 54%
(72). Therefore, AVS is essential to direct appropriate
therapy in patients with PA who seek a potential
surgical cure. CT is particularly useful, however,
for detecting larger lesions (e.g., >2.5 cm) that may
warrant consideration for removal based on malignant
potential and also for localizing the right adrenal vein
as it enters into the inferior vena cava, thus aiding
cannulation of the vein during AVS (73, 74).
3.1.REMARKS
Magnetic resonance imaging (MRI) has no advantage
over CT in subtype evaluation of primary aldosteronism, being more expensive and having less
spatial resolution than CT.
3.2. We recommend that, when surgical treatment is
practicable and desired by the patient, the distinction
between unilateral and bilateral adrenal disease
be made by AVS by an experienced radiologist
(Figure 1). (1|
)
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
3.2.EVIDENCE
14
Lateralization of the source of the excessive
aldosterone secretion is critical to guide the
management of PA. Distinguishing between
unilateral and bilateral disease is important because
unilateral adrenalectomy in patients with APA or
unilateral adrenal hyperplasia (UAH) results in
normalization of hypokalemia in all; hypertension is
improved in all and cured in 30% to 60% (46, 75, 76).
In bilateral IHA and GRA, unilateral or bilateral
adrenalectomy seldom corrects the hypertension
(77–81), and medical therapy is the treatment of
choice (82). Unilateral disease may be treated
medically if the patient declines or is not a candidate
for surgery.
Imaging cannot reliably visualize microadenomas or
distinguish incidentalomas from aldosteroneproducing adenomas with confidence (71), making
AVS the most accurate means of differentiating
unilateral from bilateral forms of PA. AVS is
expensive and invasive, and so it is highly desirable to
avoid this test in patients who do not have PA (83).
Since ARR testing can be associated with false
positives, confirmatory testing should eliminate the
potential for patients with false positive ARR to
undergo AVS.
The sensitivity and specificity of AVS (95% and
100%, respectively) for detecting unilateral aldosterone excess are superior to that of adrenal CT
(78% and 75%, respectively) (62, 71, 72).
Importantly, CT has the potential to be frankly
misleading by demonstrating unilateral nodules in
patients with bilateral disease and thereby to lead to
inappropriate surgery.
AVS is the reference standard test to differentiate
unilateral (APA or UAH) from bilateral disease
(IHA) in patients with PA (62, 71). Although AVS
can be a difficult procedure, especially in terms of
successfully cannulating the right adrenal vein
(which is smaller than the left and usually empties
directly into the inferior vena cava rather than the
renal vein), the success rate usually improves quickly
as the angiographer becomes more experienced.
According to a review of 47 reports, the success rate
for cannulating the right adrenal vein in 384 patients
was 74% (82). With experience, the success rate
increased to 90%–96% (71, 73, 74, 84). The addition
of rapid intraprocedural measurement of adrenal vein
cortisol concentrations has facilitated improved
accuracy of catheter placement in AVS (85). Some
centers perform AVS in all patients who have the
diagnosis of PA (62), and others advocate its selective
use (e.g., AVS may not be needed in patients younger
than age 40 with solitary unilateral apparent adenoma
on CT scan) (71, 86).
At centers with experienced AVS radiologists, the
complication rate is 2.5% or lower (71, 73). The risk
of adrenal hemorrhage can be minimized by
employing a radiologist skilled in the technique, and
by avoiding adrenal venography and limiting use of
contrast to the smallest amounts necessary to assess
the catheter tip position (74).Where there is a
clinical suspicion of a pro-coagulant disorder, the risk
of thrombo-embolism may be reduced by performing
tests for such conditions before the procedure and
administering heparin after the procedure in patients
at risk.
3.2.VALUES
Our recommendation to pursue AVS in the subtype
evaluation of the patient with PA who is a candidate
for surgery places a high value on avoiding the risk of
an unnecessary unilateral adrenalectomy based on
adrenal CT and a relatively low value on avoiding the
potential complications of AVS.
3.2.REMARKS
A radiologist experienced with and dedicated to AVS
is needed to implement this recommendation.
The criteria used to determine lateralization of
aldosterone hypersecretion depend on whether the
sampling is done under cosyntropin administration.
Dividing the right and left adrenal vein plasma
aldosterone concentrations (PACs) by their
respective cortisol concentrations corrects for
dilutional effects of the inferior phrenic vein flowing
into the left adrenal vein and, if suboptimally
sampled, of IVC flow into the right adrenal vein.
These are termed “cortisol-corrected aldosterone
ratios.” With continuous cosyntropin administration,
a cut-off of the cortisol-corrected aldosterone ratio
Some investigators consider a cortisol-corrected
aldosterone lateralization ratio (high to low side) of
more than 2:1 in the absence of cosyntropin as
consistent with unilateral disease (83). Other
groups rely primarily on comparing the adrenal
vein aldosterone-cortisol ratios to those in a
simultaneously collected peripheral venous sample
(62). When the aldosterone-cortisol ratio from an
adrenal vein is significantly (usually at least 2.5 times)
greater than that the peripheral vein (cubital fossa or
IVC), and the aldosterone-cortisol ratio in the
contralateral adrenal vein is no higher than
peripheral (indicating contralateral suppression), the
ratio is considered to show lateralization, an
indication that unilateral adrenalectomy should cure
or improve the hypertension.
Cosyntropin use
If cosyntropin infusion is not used, AVS should be
performed in the morning hours following overnight
recumbency. This approach avoids the confounding
effects of changes in posture on aldosterone levels in
patients with angiotensin II-responsive varieties of
PA and takes advantage of the effect of high early
morning endogenous ACTH levels on aldosterone
production in all subtypes of PA (74).
If cosyntropin infusion is used, it may be continuous
or bolus. For continuous cosyntropin, an infusion of
50 µg of cosyntropin per hour is begun 30 minutes
before adrenal vein catheterization and continued
throughout the procedure (71, 81, 84). The bolus
cosyntropin technique involves AVS before and after
the intravenous administration of 250 µg of
cosyntropin. However, some groups have suggested
that when given as a bolus injection and when the
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
There are three protocols for AVS: a) unstimulated
sequential or simultaneous bilateral AVS, b)
unstimulated sequential or simultaneous bilateral
AVS followed by bolus cosyntropin-stimulated
sequential or simultaneous bilateral AVS, and c)
continuous cosyntropin infusion with sequential
bilateral AVS. Simultaneous bilateral AVS is difficult
to perform and is not used at most centers. Many
groups advocate the use of continuous cosyntropin
infusion during AVS a) to minimize stress-induced
fluctuations in aldosterone secretion during
nonsimultaneous (sequential) AVS, b) to maximize
the gradient in cortisol from adrenal vein to inferior
vena cava and thus confirm successful sampling of the
adrenal vein, and c) to maximize the secretion of
aldosterone from an APA (71, 81, 84, 87) and thus
avoid the risk of sampling during a relatively
quiescent phase of aldosterone secretion.
from high-side to low-side more than 4:1 is used to
indicate unilateral aldosterone excess (71); a ratio less
than 3:1 is suggestive of bilateral aldosterone
hypersecretion (71). With these cut-offs, AVS for
detecting unilateral aldosterone hypersecretion (APA
or UAH) has a sensitivity of 95% and specificity of
100% (71). Patients with lateralization ratios
between 3:1 and 4:1 may have either unilateral or
bilateral disease, and the AVS results must be
interpreted in conjunction with the clinical setting,
CT scan, and ancillary tests.
15
adrenal veins are sampled simultaneously,
cosyntropin administration does not improve the
diagnostic accuracy of AVS and that cosyntropin may
in fact increase secretion from the non-adenomatous
gland to a greater degree than from the APA (88).
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
Catheterization
The adrenal veins are catheterized through the
percutaneous femoral vein approach, and the position
of the catheter tip is verified by gentle injection of a
small amount of nonionic contrast medium and
radiographic documentation (73). Blood is obtained
from both adrenal veins and a peripheral vein, e.g.,
cubital fossa or iliac vein, and labeled peripheral and
assayed for aldosterone and cortisol concentrations. To
be sure there is no cross-contamination, the
“peripheral” sample should be obtained from a cubital
or iliac vein. The venous sample from the left side
typically is obtained with the catheter tip at the
junction of the inferior phrenic and left adrenal vein.
The right adrenal vein may be especially difficult to
catheterize because it is short and enters the IVC at an
acute angle (84). The cortisol concentrations from the
adrenal veins and peripheral vein are used to confirm
successful catheterization. The adrenal/peripheral vein
cortisol ratio is typically more than 10:1 with the
continuous cosyntropin infusion protocol (71) and
more than 3:1 without the use of cosyntropin (43).
16
Unsuccessful adrenal venous sampling
When both adrenal veins are not successfully
catheterized, the clinician may (1) repeat AVS; (2)
treat the patient with MR antagonsist; (3) consider
surgery based the findings of other studies (e.g.,
adrenal CT). Additional studies that may guide the
clinician in this setting include posture stimulation
test and iodocholesterol scintigraphy.
(89). In a review of 16 published reports, the accuracy
of the posture stimulation test was 85% in 246
patients with surgically verified APA (82). The lack
of accuracy is explained by the fact that some APAs
are sensitive to angiotensin II and some patients with
IHA have diurnal variation in aldosterone secretion
(90). Thus, the posture stimulation test—particularly
if it shows lack of responsiveness (consistent with
angiotensin II–unresponsive APA or familial
hyperaldosteronism type I (FH-I), with the latter
readily confirmed or excluded by genetic testing)—
may serve an ancillary role, for example, in those
patients for whom AVS was unsuccessful and CT
shows a unilateral adrenal mass (91, 92).
Iodocholesterol scintigraphy. [131I]-19-iodocholesterol
scintigraphy was first used in the early 1970s (93), and
an improved agent, [6β-131I]iodomethyl-19norcholesterol (NP-59), was introduced in 1977 (94).
The NP-59 scan, performed with dexamethasone
suppression, had the putative advantage of correlating
function with anatomical abnormalities. However,
the sensitivity of this test depends heavily on the size
of the adenoma (95, 96). Because tracer uptake was
poor in adenomas smaller than 1.5 cm in diameter,
this method often is not helpful in interpreting
micronodular findings obtained with high-resolution
CT (97) and rarely plays a role in subtype evaluation.
Currently it is no longer used in most centers.
18-Hydroxycorticosterone levels. 18-Hydroxycorti-
costerone (18-OHB) is formed by 18-hydroxylation of
corticosterone. Patients with APA generally have
recumbent plasma 18-OHB levels greater than 100
ng/dL at 8:00 a.m., whereas patients with IHA have
levels that are usually less than 100 ng/dL (98).
However, this test lacks the accuracy needed to guide
the clinician in the subtype evaluation of PA (82).
Posture stimulation test. In patients with unsuccessful
AVS and with a CT scan showing a unilateral adrenal
mass, some experts use the posture stimulation test.
This test, developed in the 1970s, was based on the
finding that the PAC in patients with APA showed
diurnal variation and was relatively unaffected by
changes in angiotensin II levels, whereas IHA was
characterized by enhanced sensitivity to a small
change in angiotensin II that occurred with standing
3.3. In patients with onset of confirmed PA earlier
than at 20 years of age and in those who have a family
history of PA or of strokes at young age, we suggest
genetic testing for GRA (Figure 1). (2|
)
3.3.EVIDENCE
Testing for familial forms of PA: FH-I [GRA]
The FH-I syndrome is inherited in an autosomal
dominant fashion and is responsible for fewer than
1% of cases of PA (99). GRA presentation is highly
variable, with some patients presenting with normal
blood pressure and some characterized by aldosterone
excess, suppressed PRA, and hypertension of early
onset that is usually severe and refractory to
conventional antihypertensive therapies.
Genetic testing by either Southern blot (102) or long
polymerase chain reaction (103) techniques is
sensitive and specific for GRA and obviates the need
to measure the urinary levels of 18-oxocortisol and
18-hydroxy-cortisol or to perform dexamethasone
suppression testing, both of which may be misleading
(104). Genetic testing for GRA should be considered
for PA patients with a family history of PA or of
strokes at a young age (101, 105), or with an onset at
a young age (e.g., <20 years).
Testing for familial forms of PA: FH-II
FH-II is an autosomal dominant disorder and possibly
genetically heterogeneous (106). Unlike FH-I, the
hyperaldosteronism in FH type II does not suppress
Finally, aldosterone-producing adenoma may rarely
but on occasion be seen in multiple endocrine
neoplasia type 1.
4.0. TREATMENT
4.1. We recommend that unilateral laparoscopic
adrenalectomy be offered to patients with documented
unilateral PA (i.e., APA or UAH) (Figure 1).
(1|
) If a patient is unable or unwilling to
undergo surgery, we recommend medical treatment
with an mineralocorticoid receptor antagonist
(Figure 1). (1|
)
4.1.EVIDENCE
Unilateral laparoscopic adrenalectomy is used in
patients with unilateral PA because blood pressure
and serum potassium concentrations improve in
nearly 100% of patients postoperatively (76,
110–114). Hypertension is cured (defined as BP
<140/90 mm Hg without the aid of antihypertensive
drugs) in about 50% (range 35%–60%) of patients
with APA after unilateral adrenalectomy (75, 110),
with a ‘cure’ rate as high as 56%-77% when the cure
threshold was blood pressure <160/95 mm Hg (46,
115, 116). There is no high quality evidence linking
adrenalectomy with improved quality of life,
morbidity, or mortality as studies of this nature have
not, to our knowledge, been published.
Factors associated with resolution of hypertension in
the post-operative period include having one or no
first-degree relative with hypertension and preoperative use of two or fewer antihypertensive drugs
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
Some studies suggest a high pretest probability for
GRA in children or young adults with severe or
resistant hypertension and a positive family history of
early onset hypertension and/or premature
hemorrhagic stroke (100, 101). In the study by Dluhy
and colleagues (100), 50% of children under 18
years of age with GRA had moderate or severe
hypertension (blood pressure >99th percentile for age
and sex) at diagnosis. Moreover, Litchfield et al.
(101) reported in 376 patients from 27 genetically
proven GRA pedigrees that 48% of all GRA
pedigrees and 18% of all GRA patients had
cerebrovascular complications, with the mean age at
the time of the initial event being 32 ± 11.3 years.
Seventy percent of events were hemorrhagic strokes
with an overall case fatality rate of 61% (101). The
study design used in these reports does not allow
estimation of the yield of new GRA patients that case
detection could have in such populations.
with dexamethasone, and GRA mutation testing is
negative (107). FH-II families may have APA, IHA,
or both and are clinically indistinguishable from
patients with apparent nonfamilial PA (108).
Although FH-II is more common than FH-I,
accounting for at least 7% of patients with PA in one
series, its prevalence is unknown (108). The
molecular basis for FH-II is unclear, although several
linkage analyses have shown an association with
chromosomal region 7p22 (106, 109).
17
(76). Other factors have been reported to predict
cure, but have only been evaluated by univariate
analysis or when the cut-off for blood pressure
resolution was <160/95 mm Hg (46, 110, 113):
duration of hypertension <5 years (46, 47, 75, 76),
higher PAC:PRA ratio preoperatively (75, 76),
higher urinary aldosterone secretion (75, 76), or
positive pre-operative response to spironolactone (75,
111). The most common reasons for persistently
increased blood pressure after adrenalectomy are
coexistent hypertension of unknown cause (46, 76)
and older age and/or longer duration of hypertension.
4.1.VALUES
Our recommendation to subject patients with unilateral
adrenal disease to laparoscopic adrenalectomy in
preference to other methods of treatment places a high
value on reduction of blood pressure and/or the
number of medications necessary to control blood
pressure, on normalization of endogenous aldosterone
secretion, and on the resolution of hypokalemia.
This benefit is far greater than the risks of surgery and
post-operative management, which are extremely low.
4.1.REMARKS
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
As compared with open adrenalectomy, laparoscopic
adrenalectomy is associated with shorter hospital
stays and fewer complications (112, 117, 118).
Because AVS is able to identify only which gland
(and not which part of the gland) is overproducing
aldosterone, partial adrenalectomy (removal of an
adenoma leaving the remaining adrenal intact) may
result in persistent hypertension; continued elevation
of PAC is found in up to 10% of patients with
unilateral APA, and 27% of extirpated adrenal glands
are found to contain multiple nodules (119).
18
Medical management is recommended for patients
who do not undergo surgery. In a retrospective study
of 24 patients with APA who were treated for 5
years with spironolactone or amiloride, systolic
and diastolic BP decreased from an average of
175/106 to 129/79 mm Hg (120) with 83% of these
patients requiring additional antihypertensive
medication to achieve this result. Furthermore,
several of the patients experienced side effects
from the spironolactone therapy including breast
tenderness (54%), breast engorgement (33%), muscle
cramps (29%), and decreased libido (13%). In the
long-term, adrenalectomy is more cost-effective than
lifelong medical therapy for patients with unilateral
primary aldosteronism (121).
Therefore, because unilateral laparoscopic adrenalectomy can either eliminate the need for medication
or reduce medication-related side effects, it is the
preferred procedure for the treatment of unilateral
disease in patients with PA.
This recommendation requires the availability of a
surgeon experienced in laparoscopic adrenalectomy.
Preoperative management
In the patient scheduled for surgery both hypertension and hypokalemia should be well controlled
preoperatively. Obtaining such control may require a
delay in surgery and the addition of an MR
antagonist.
Postoperative management
Plasma aldosterone and renin activity levels should be
measured shortly after surgery as an early indication of
biochemical response (114), and on postoperative day
1 potassium supplementation should be withdrawn,
spironolactone discontinued, and antihypertensive
therapy reduced, if appropriate (122).
Postoperative intravenous fluids should be normal
saline without potassium chloride unless serum
potassium levels remain very low (i.e., <3.0 mmol/L),
and during the first few weeks after surgery a generous
sodium diet should be recommended to avoid the
hyperkalemia that can develop from hypoaldosteronism due to chronic contralateral adrenal
gland suppression (122). In rare instances, temporary
fludrocortisone therapy may be required.
Blood pressure typically normalizes or shows
maximum improvement in 1–6 months after
unilateral adrenalectomy for unilateral APA, but can
continue to fall for up to 1 year in some patients.
Some investigators have employed postoperative
fludrocortisone suppression testing (performed at least
3 months after surgery to permit recovery of the
contralateral gland) to assess whether the PA has
been cured from a biochemical perspective (123).
4.2. In patients with PA due to bilateral adrenal
disease, we recommend medical treatment with
an MR antagonist (1|
); we suggest
spironolactone as the primary agent with eplerenone
as an alternative. (2|
) (Figure 1)
4.2.EVIDENCE
Bilateral adrenal disease includes idiopathic adrenal
hyperplasia, bilateral APA, and GRA. In 99 surgically
treated patients with IHA reported in the literature,
the hypertension cure rate was only 19% after
unilateral or bilateral adrenalectomy (77-81). No
randomized placebo-controlled trials have evaluated
the relative efficacy of drugs in the treatment of PA.
However, the pathophysiology of PA due to bilateral
adrenal hyperplasia and longstanding clinical
experience suggest several pharmacological targets.
Spironolactone
For more than 4 decades, the MR antagonist
spironolactone has been the agent of choice in the
medical treatment of PA. Several observational
studies in patients with IHA (combined N=122) have
reported a mean reduction in systolic blood pressure
of 25% and diastolic blood pressure of 22% in
response to spironolactone 50–400 mg per day for 1 to
96 months (124-130). In a study of 28 hypertensive
subjects with an ARR >750 pmol/l (27 ng/dl) per
ng/mL per hour who failed to suppress their PAC after
salt loading and without evidence of adenoma on
adrenal CT scan, spironolactone therapy (25–50
mg/day) reduced the need for antihypertensive drugs
by -0.5 (from a mean of 2.3 to 1.8 drugs) drugs, as well
as reducing systolic blood pressure by -15 mm Hg
(from a mean of 161 to 146 mm Hg) and diastolic
blood pressure by -8 mm Hg (from a mean of 91 to 83
mm Hg); 48% of subjects achieved a blood pressure
<140/90 mm Hg, and about half were able to be
The incidence of gynecomastia with spironolactone
therapy is dose-related, with one study reporting an
incidence after 6 months of 6.9% at a dose <50 mg
per day and 52% at a dose >150 mg per day (132).
The exact incidence of menstrual disturbances in
premenopausal women with spironolactone therapy
is unknown. Where available, canrenone (an
active metabolite of spironolactone) or potassium
canrenoate, its open E-ring water soluble congener,
might be considered, in that they possibly have fewer
sex steroid-related side effects. In addition, a small
dose of a thiazide diuretic, triamterine, or amiloride
can be added to attempt to avoid a higher dose of
spironolactone, which may cause side effects.
Eplerenone
Eplerenone is a newer, selective MR antagonist
without anti-androgen and progesterone agonist
effects (133), thus reducing the rate of adverse
endocrine side effects. It has been approved for the
treatment of primary (essential) hypertension (134,
135) in the United States and Japan, and for heart
failure after myocardial infarction (136) in the
United States and a number of other countries.
Eplerenone has 60% of the MR antagonist potency of
spironolactone; its better tolerability profile needs to
be balanced against its higher cost and the lack of
current clinical trial evidence for its use in PA.
Reflecting its shorter half-life, eplerenone should be
given twice daily for optimal effect.
Other agents
Upregulation of distal tubular sodium epithelial
channel activity is a major mechanism whereby
aldosterone exerts its actions on sodium and
potassium handling. Of the available epithelial
sodium channel antagonists (amiloride and
triamterene), amiloride has been the most studied as
a mode of treatment for PA. Although less efficacious
than spironolactone, amiloride may be useful (28,
137). Being a potassium-sparing diuretic, amiloride
can ameliorate both hypertension and hypokalemia
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
MR antagonists
MR antagonists appear to be effective at controlling
blood pressure and to provide blood pressureindependent target organ protection.
managed with spironolactone monotherapy (131).
The dose of spironolactone employed in that study
was much lower than previously considered necessary
for the treatment of PA.
19
in patients with PA and is generally well tolerated,
lacking the sex steroid-related side effects of
spironolactone, but without the beneficial effects on
endothelial function (138, 139).
Calcium channel blockers, ACE inhibitors, and
angiotensin receptor blockers have been evaluated in
very few patients with PA, and in general they are
antihypertensive without a major effect on aldosterone excess. Supportive studies are small and
methodologically weak, and have not measured
patient-important outcomes. Aldosterone synthase
inhibitors may play a role in the future.
4.2.VALUES
This recommendation places a relatively higher value
on reduction of blood pressure normalization of serum
potassium concentrations and abrogation of the
vascular, cardiac, and renal effects of aldosterone with
the minimum number of pharmacological agents, and
a relatively lower value on side effects such as
gynecomastia and erectile dysfunction in men and
menstrual irregularities in women. Eplerenone, given
its selectivity and despite its cost, is an alternative if the
side effects of spironolactone prove difficult to tolerate.
4.3.EVIDENCE
GRA should be treated medically with a glucocorticoid
to partially suppress pituitary ACTH secretion. We
recommend use of a synthetic glucocorticoid that is
longer acting than hydrocortisone, such as
dexamethasone or prednisone, to suppress ACTH
secretion. Ideally, the glucocorticoid should be taken at
bedtime to suppress the early morning ACTH surge.
Plasma renin activity and aldosterone concentrations
may be helpful in assessing the effectiveness of
treatment and the prevention of overtreatment.
Over-treatment with exogenous steroids must be
avoided; iatrogenic Cushing’s syndrome and impaired
linear growth in children have resulted from such
overdosing (100). In general, the lowest possible dose
of glucocorticoid that normalizes blood pressure
and/or serum potassium concentration should be used
(74). Treatment with a glucocorticoid may not always
normalize blood pressure, and addition of an MR
antagonist should be considered in these cases.
The use of eplerenone may be preferred in the case
of affected children, in whom there may be
concerns with respect to growth retardation and
anti-androgenic effects of glucocorticoids and
spironolactone, respectively.
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
4.2.REMARKS
20
The starting dose for spironolactone should be 12.5 to
25 mg daily in a single dose. The lowest effective dose
should be found by very gradually titrating upward if
necessary to a maximum dose of 100 mg per day. The
starting dose for eplerenone is 25 mg once or twice
daily. In patients with stage III chronic kidney disease
(i.e., GFR <60 mL/min/1.73m2), spironolactone and
eplerenone may be used with caution because of the
risk of hyperkalemia, but MR antagonists should be
avoided in those with stage IV disease.
4.3. In patients with GRA, we recommend the use of
the lowest dose of glucocorticoid that can normalize
blood pressure and potassium levels rather than firstline treatment with an MR antagonist (Figure 1).
(1|
)
4.3.VALUES
The treatment of GRA places a high value on
preventing the potential consequences of
hyperaldosteronism and a lower value on the possible
side effects of chronic glucocorticoid administration.
4.3.REMARKS
The starting dose of dexamethasone in adults is 0.125
to 0.25 mg daily. The starting dose of prednisone is
2.5 to 5 mg daily. For each, treatment is usually
administered at bedtime.
References
1.
2.
3.
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y,
Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry
D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N,
Mason J, Middleton P, Mrukowicz J, O’Connell D,
Oxman AD, Phillips B, Schunemann HJ, Edejer TT,
Varonen H, Vist GE, Williams JW, Jr., Zaza S 2004
Grading quality of evidence and strength of
recommendations. BMJ 328:1490
Swiglo BA, Murad MH, Schünemann HJ, Kunz R,
Vigersky RA, Guyatt GH, Montori VM 2008 A case for
clarity, consistency, and helpfulness: state-of-the-art clinical
practice guidelines in endocrinology using the grading of
recommendations, assessment, development, and
evaluation system. J Clin Endocrinol Metab 93:666–73
Andersen GS, Toftdahl DB, Lund JO, Strandgaard S,
Nielsen
PE
1988 The incidence rate of
phaeochromocytoma and Conn’s syndrome in Denmark,
1977-1981. J Hum Hypertens 2:187–9
Berglund G, Andersson O, Wilhelmsen L 1976
Prevalence of primary and secondary hypertension: studies
in a random population sample. Br Med J 2:554–6
5.
Fishman LM, Kuchel O, Liddle GW, Michelakis AM,
Gordon RD, Chick WT 1968 Incidence of primary
aldosteronism uncomplicated “essential” hypertension. A
prospective study with elevated aldosterone secretion and
suppressed plasma renin activity used as diagnostic criteria.
JAMA 205:497–502
6.
Kaplan NM 1967 Hypokalemia in the hypertensive
patient, with observations on the incidence of primary
aldosteronism. Ann Intern Med 66:1079-90
7.
Streeten DH, Tomycz N, Anderson GH 1979 Reliability
of screening methods for the diagnosis of primary
aldosteronism. Am J Med 67:403–13
14.
Lim PO, Dow E, Brennan G, Jung RT, MacDonald TM
2000 High prevalence of primary aldosteronism in the
Tayside hypertension clinic population. J Hum Hypertens
14:311–5
15.
Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF,
Jr. 2000 Prevalence of primary aldosteronism among Asian
hypertensive patients in Singapore. J Clin Endocrinol
Metab 85:2854–9
16.
Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F,
Montero J, Huete A, Gederlini A, Fardella CE 2003
Primary aldosteronism and hypertensive disease.
Hypertension 42:161–5
17.
Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B,
Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario
M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A,
Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni
D, Rossi E, Boscaro M, Pessina AC, Mantero F 2006 A
prospective study of the prevalence of primary
aldosteronism in 1,125 hypertensive patients. J Am Coll
Cardiol 48:2293–300
18.
Schwartz GL, Turner ST 2005 Screening for primary
aldosteronism in essential hypertension: diagnostic
accuracy of the ratio of plasma aldosterone concentration to
plasma renin activity. Clin Chem 51:386–94
19.
Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon
RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF,
Jr. 2004 Increased diagnosis of primary aldosteronism,
including surgically correctable forms, in centers from five
continents. J Clin Endocrinol Metab 89:1045–50
20.
Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C,
Giacchetti G, Letizia C, Maccario M, Mannelli M,
Matterello MJ, Montemurro D, Palumbo G, Rizzoni D,
Rossi E, Pessina AC, Mantero F 2006 Renal damage in
primary aldosteronism: results of the PAPY Study.
Hypertension 48:232–8
8.
Tucker RM, Labarthe DR 1977 Frequency of surgical
treatment for hypertension in adults at the Mayo Clinic
from 1973 through 1975. Mayo Clin Proc 52:549–5
9.
Sinclair AM, Isles CG, Brown I, Cameron H, Murray
GD, Robertson JW 1987 Secondary hypertension in a
blood pressure clinic. Arch Intern Med 147:1289–93
21.
Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto
J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori
A, Montero J 2000 Primary hyperaldosteronism in essential
hypertensives: prevalence, biochemical profile, and
molecular biology. J Clin Endocrinol Metab 85:1863–7
Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME,
Mourad JJ 2005 Evidence for an increased rate of
cardiovascular events in patients with primary
aldosteronism. J Am Coll Cardiol 45:1243–8
22.
Stowasser M, Sharman J, Leano R, Gordon RD, Ward G,
Cowley D, Marwick TH 2005 Evidence for abnormal left
ventricular structure and function in normotensive
individuals with familial hyperaldosteronism type I. J Clin
Endocrinol Metab 90:5070–6
23.
Rossi E, Regolisti G, Negro A, Sani C, Davoli S,
Perazzoli F 2002 High prevalence of primary aldosteronism
using postcaptopril plasma aldosterone to renin ratio as a
screening test among Italian hypertensives. Am J Hypertens
15:896–902
10.
11.
Gordon RD, Stowasser M, Tunny TJ, Klemm SA,
Rutherford JC 1994 High incidence of primary
aldosteronism in 199 patients referred with hypertension.
Clin Exp Pharmacol Physiol 21:315–8
12.
Grim CE, Weinberger MH, Higgins JT, Kramer NJ 1977
Diagnosis of secondary forms of hypertension. A
comprehensive protocol. JAMA 237:1331–5
13.
Hamlet SM, Tunny TJ, Woodland E, Gordon RD 1985 Is
aldosterone/renin ratio useful to screen a hypertensive
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
4.
population for primary aldosteronism? Clin Exp Pharmacol
Physiol 12:249–52
21
24.
25.
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
Williams JS, Williams GH, Raji A, Jeunemaitre X,
Brown NJ, Hopkins PN, Conlin PR 2006 Prevalence of
primary hyperaldosteronism in mild to moderate
hypertension without hypokalaemia. J Hum Hypertens
20:129–36
Hiramatsu K, Yamada T, Yukimura Y, Komiya I,
Ichikawa K, Ishihara M, Nagata H, Izumiyama T 1981 A
screening test to identify aldosterone-producing adenoma
by measuring plasma renin activity. Results in hypertensive
patients. Arch Intern Med 141:1589–93
41.
McKenna TJ, Sequeira SJ, Heffernan A, Chambers J,
Cunningham S 1991 Diagnosis under random conditions of
all disorders of the renin-angiotensin-aldosterone axis,
including primary hyperaldosteronism. J Clin Endocrinol
Metab 73:952–7
42.
Stowasser M, Gordon RD, Gunasekera TG, Cowley DC,
Ward G, Archibald C, Smithers BM 2003 High rate of
detection of primary aldosteronism, including surgically
treatable forms, after ‘non-selective’ screening of
hypertensive patients. J Hypertens 21:2149–57
43.
Gordon RD 1995 Primary aldosteronism. J Endocrinol
Invest 18:495–511
44.
Stowasser M, Gordon RD 2004 The aldosterone-renin
ratio for screening for primary aldosteronism. The
Endocrinologist 14:267–76
45.
Tanabe A, Naruse M, Takagi S, Tsuchiya K, Imaki T,
Takano K 2003 Variability in the renin/aldosterone profile
under random and standardized sampling conditions in
primary aldosteronism. J Clin Endocrinol Metab
88:2489–94
46.
Celen O, O’Brien MJ, Melby JC, Beazley RM 1996
Factors influencing outcome of surgery for primary
aldosteronism. Arch Surg 131:646–50
47.
Streeten DH, Anderson GH, Jr., Wagner S 1990 Effect of
age on response of secondary hypertension to specific
treatment. Am J Hypertens 3:360–5
48.
Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F,
Chiandussi L, Veglio F 2002 Drug effects on
aldosterone/plasma renin activity ratio in primary
aldosteronism. Hypertension 40:897–902
49.
Montori VM, Schwartz GL, Chapman AB, Boerwinkle E,
Turner ST 2001 Validity of the aldosterone-renin ratio
used to screen for primary aldosteronism. Mayo Clin Proc
76:877–82
50.
Sealey JE, Laragh JH 1975 Radioimmunoassay of plasma
renin activity. Semin Nucl Med 5:189–202
51.
Schirpenbach C, Seiler L, Maser-Gluth C, Beuschlein F,
Reincke M, Bidlingmaier M 2006 Automated
chemiluminescence-immunoassay for aldosterone during
dynamic testing: comparison to radioimmunoassays with
and without extraction steps. Clin Chem 52:1749–55
52.
Guo T, Taylor RL, Singh RJ, Soldin SJ 2006
Simultaneous determination of 12 steroids by isotope
dilution liquid chromatography-photospray ionization
tandem mass spectrometry. Clin Chim Acta 372:76–82
53.
Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM,
Kong AP 2005 The use of aldosterone-renin ratio as a
diagnostic test for primary hyperaldosteronism and its test
characteristics under different conditions of blood
sampling. J Clin Endocrinol Metab 90:72–8
Benchetrit S, Bernheim J, Podjarny E 2002
Normokalemic hyperaldosteronism in patients with
resistant hypertension. Isr Med Assoc J 4:17–20
27.
Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB,
Weissmann P 2002 Hyperaldosteronism among black and
white subjects with resistant hypertension. Hypertension
40:892–6
28.
Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl
NP 2004 Low-renin status in therapy-resistant
hypertension: a clue to efficient treatment. J Hypertens
22:2217–26
Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC 2001
Screening for primary aldosteronism without discontinuing
hypertensive medications: plasma aldosterone-renin ratio.
Am J Kidney Dis 37:699–705
30.
Goodfriend TL, Calhoun DA 2004 Resistant
hypertension, obesity, sleep apnea, and aldosterone: theory
and therapy. Hypertension 43:518–24
31.
Calhoun DA, Nishizaka MK, Zaman MA, Harding SM
2004 Aldosterone excretion among subjects with resistant
hypertension and symptoms of sleep apnea. Chest
125:112–7
32.
Aso Y, Homma Y 1992 A survey on incidental adrenal
tumors in Japan. J Urol 147:1478–81
33.
Barzon L, Sonino N, Fallo F, Palu G, Boscaro M 2003
Prevalence and natural history of adrenal incidentalomas.
Eur J Endocrinol 149:273–85
34.
Bulow B, Ahren B 2002 Adrenal incidentaloma-experience of a standardized diagnostic programme in the
Swedish prospective study. J Intern Med 252:239–46
35.
22
40.
26.
29.
36.
37.
38.
39.
review of the literature. Endocrinol Metab Clin North Am
31:619–32, xi
Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky
J, Jr. 2003 Prevalence of primary hyperaldosteronism in
moderate to severe hypertension in the Central Europe
region. J Hum Hypertens 17:349–52
Caplan RH, Strutt PJ, Wickus GG 1994 Subclinical
hormone secretion by incidentally discovered adrenal
masses. Arch Surg 129:291–6
Kim HY, Kim SG, Lee KW, Seo JA, Kim NH, Choi KM,
Baik SH, Choi DS 2005 Clinical study of adrenal
incidentaloma in Korea. Korean J Intern Med 20:303–9
Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM,
Ali A, Giovagnetti M, Opocher G, Angeli A 2000 A
survey on adrenal incidentaloma in Italy. Study Group on
Adrenal Tumors of the Italian Society of Endocrinology. J
Clin Endocrinol Metab 85:637–44
Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero
GR, Palatini P, Pessina AC 1996 Changes in left
ventricular anatomy and function in hypertension and
primary aldosteronism. Hypertension 27:1039–45
Montori VM, Young WF, Jr. 2002 Use of plasma
aldosterone concentration-to-plasma renin activity ratio as
a screening test for primary aldosteronism. A systematic
54.
Young WF, Jr. 1997 Primary aldosteronism: update on
diagnosis and treatment. The Endocrinologist 7:213–21
69.
Young WF, Jr. 2007 Clinical practice. The incidentally
discovered adrenal mass. N Engl J Med 356:601–10
55.
Young WF 2007 Primary aldosteronism: renaissance of a
syndrome. Clin Endocrinol (Oxf) 66:607–18
70.
56.
Stowasser M, Gordon RD 2004 Primary aldosteronism—
careful investigation is essential and rewarding. Mol Cell
Endocrinol 217:33–9
Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro
B 1995 Incidentally discovered adrenal masses. Endocr Rev
16:460–84
71.
Young WF, Stanson AW, Thompson GB, Grant CS,
Farley DR, van Heerden JA 2004 Role for adrenal venous
sampling in primary aldosteronism. Surgery 136:1227–35
72.
Nwariaku FE, Miller BS, Auchus R, Holt S, Watumull L,
Dolmatch B, Nesbitt S, Vongpatanasin W, Victor R,
Wians F, Livingston E, Snyder WH, 3rd 2006 Primary
hyperaldosteronism: effect of adrenal vein sampling on
surgical outcome. Arch Surg 141:497–502
73.
Daunt N 2005 Adrenal vein sampling: how to make it
quick, easy, and successful. Radiographics 25 (suppl
1):S143–58
74.
Stowasser
M,
Gordon
RD
2001 Familial
hyperaldosteronism. J Steroid Biochem Mol Biol 78:215–29
75.
Meyer A, Brabant G, Behrend M 2005 Long-term followup after adrenalectomy for primary aldosteronism. World J
Surg 29:155–9
76.
Sawka AM, Young WF, Thompson GB, Grant CS, Farley
DR, Leibson C, van Heerden JA 2001 Primary
aldosteronism: factors associated with normalization of
blood pressure after surgery. Ann Intern Med 135:258–61
57.
58.
Giacchetti G, Ronconi V, Lucarelli G, Boscaro M,
Mantero F 2006 Analysis of screening and confirmatory
tests in the diagnosis of primary aldosteronism: need for a
standardized protocol. J Hypertens 24:737–45
Rossi GP, Belfiore A, Bernini G, Desideri G, Fabris B,
Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci
F, Mannelli M, Montemurro D, Palumbo G, Rizzoni D,
Rossi E, Semplicini A, Agabiti-Rosei E, Pessina AC,
Mantero F 2007 Prospective evaluation of the saline
infusion test for excluding primary aldosteronism due to
aldosterone-producing adenoma. J Hypertens 25:1433–42
Holland OB, Brown H, Kuhnert L, Fairchild C, Risk M,
Gomez-Sanchez CE 1984 Further evaluation of saline
infusion for the diagnosis of primary aldosteronism.
Hypertension 6:717–23
60.
Kem DC, Weinberger MH, Mayes DM, Nugent CA 1971
Saline suppression of plasma aldosterone in hypertension.
Arch Intern Med 128:380–6
61.
Gordon RD 1994 Mineralocorticoid hypertension. Lancet
344:240–3
77.
62.
Gordon RD 2001 Diagnostic investigations in primary
aldosteronism. In: Zanchetti A (ed) Clinical medicine
series on hypertension. McGraw-Hill International,
Maidenhead, UK; pp 101–111
Baer L, Sommers SC, Krakoff LR, Newton MA, Laragh
JH 1970 Pseudo-primary aldosteronism. An entity distinct
from true primary aldosteronism. Circ Res 27:203–20
78.
Gunnells JC, Jr., Bath NM, Sode J, Robinson RR 1967
Primary aldosteronism. Arch Intern Med 120:568–74
79.
Priestley JT, Ferris DO, ReMine WH, Woolner LB 1968
Primary aldosteronism: surgical management and
pathologic findings. Mayo Clin Proc 43:761–75
80.
Rhamy RK, McCoy RM, Scott HW, Jr., Fishman LM,
Michelakis AM, Liddle GW 1968 Primary aldosteronism:
experience with current diagnostic criteria and surgical
treatment in fourteen patients. Ann Surg 167:718–27
81.
Weinberger MH, Grim CE, Hollifield JW, Kem DC,
Ganguly A, Kramer NJ, Yune HY, Wellman H, Donohue
JP 1979 Primary aldosteronism: diagnosis, localization, and
treatment. Ann Intern Med 90:386–95
82.
Young WF, Jr., Klee GG 1988 Primary aldosteronism.
Diagnostic evaluation. Endocrinol Metab Clin North Am
17:367–95
83.
Rossi GP, Sacchetto A, Chiesura-Corona M, De Toni R,
Gallina M, Feltrin GP, Pessina AC 2001 Identification of
the etiology of primary aldosteronism with adrenal vein
sampling in patients with equivocal computed tomography
and magnetic resonance findings: results in 104 consecutive
cases. J Clin Endocrinol Metab 86:1083–90
84.
Doppman JL, Gill JR, Jr. 1996 Hyperaldosteronism:
sampling the adrenal veins. Radiology 198:309–12
85.
Mengozzi G, Rossato D, Bertello C, Garrone C, Milan A,
Pagni R, Veglio F, Mulatero P 2007 Rapid cortisol assay
during adrenal vein sampling in patients with primary
aldosteronism. Clin Chem 53:1968–71
63.
Gordon RD, Stowasser M, Klemm SA, Tunny TJ 1994
Primary aldosteronism and other forms of mineralocorticoid
hypertension. In: Swales J (ed) Textbook of hypertension.
Blackwell Scientific, London; pp 865–892
64.
Agharazii M, Douville P, Grose JH, Lebel M 2001
Captopril suppression versus salt loading in confirming
primary aldosteronism. Hypertension 37:1440–3
65.
Mantero F, Fallo F, Opocher G, Armanini D, Boscaro M,
Scaroni C 1981 Effect of angiotensin II and converting
enzyme inhibitor (captopril) on blood pressure, plasma
renin activity and aldosterone in primary aldosteronism.
Clin Sci (Lond) 61 Suppl 7:289s–293s
66.
Rossi GP, Belfiore A, Bernini G, Desideri G, Fabris B,
Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci
F, Mannelli M, Palumbo G, Rizzoni D, Rossi E, AgabitiRosei E, Pessina AC, Mantero F 2007 Comparison of the
captopril and the saline infusion test for excluding
aldosterone-producing adenoma. Hypertension 50:424–31
67.
68.
Hambling C, Jung RT, Gunn A, Browning MC, Bartlett
WA 1992 Re-evaluation of the captopril test for the
diagnosis of primary hyperaldosteronism. Clin Endocrinol
(Oxf) 36:499–503
Mulatero P, Bertello C, Garrone C, Rossato D, Mengozzi
G, Verhovez A, Fallo F, Veglio F 2007 Captopril test can
give misleading results in patients with suspect primary
aldosteronism. Hypertension 50:e26–7
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
59.
23
86.
87.
88.
89.
90.
91.
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
92.
24
Tan YY, Ogilvie JB, Triponez F, Caron NR, Kebebew EK,
Clark OH, Duh QY 2006 Selective use of adrenal venous
sampling in the lateralization of aldosterone-producing
adenomas. World J Surg 30:879–85
Carr CE, Cope C, Cohen DL, Fraker DL, Trerotola SO
2004 Comparison of sequential versus simultaneous
methods of adrenal venous sampling. J Vasc Interv Radiol
15:1245–50
Rossi GP, Ganzaroli C, Miotto D, De Toni R, Palumbo
G, Feltrin GP, Mantero F, Pessina AC 2006 Dynamic
testing with high-dose adrenocorticotrophic hormone does
not improve lateralization of aldosterone oversecretion in
primary aldosteronism patients. J Hypertens 24:371–9
Ganguly A, Dowdy AJ, Luetscher JA, Melada GA 1973
Anomalous postural response of plasma aldosterone
concentration in patients with aldosterone-producing
adrenal adenoma. J Clin Endocrinol Metab 36:401–4
Gordon RD, Gomez-Sanchez CE, Hamlet SM, Tunny TJ,
Klemm SA 1987 Angiotensin-responsive aldosteroneproducing adenoma masquerades as idiopathic
hyperaldosteronism (IHA: adrenal hyperplasia) or lowrenin essential hypertension. J Hypertens Suppl 5:S103–6
Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt
PJ 2003 Predicting surgically remedial primary
aldosteronism: role of adrenal scanning, posture testing, and
adrenal vein sampling. J Clin Endocrinol Metab
88:3637–44
Phillips JL, Walther MM, Pezzullo JC, Rayford W,
Choyke PL, Berman AA, Linehan WM, Doppman JL,
Gill Jr JR, Jr. 2000 Predictive value of preoperative tests in
discriminating bilateral adrenal hyperplasia from an
aldosterone-producing adrenal adenoma. J Clin Endocrinol
Metab 85:4526–33
99.
McMahon GT, Dluhy RG 2004 Glucocorticoidremediable aldosteronism. Cardiol Rev 12:44–8
100. Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R
2001 Glucocorticoid-remediable aldosteronism is associated
with severe hypertension in early childhood. J Pediatr
138:715–20
101. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP,
Dluhy RG 1998 Intracranial aneurysm and hemorrhagic
stroke in glucocorticoid-remediable aldosteronism.
Hypertension 31:445–50
102. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S,
Ulick S, Lalouel JM 1992 A chimaeric 11 betahydroxylase/aldosterone
synthase
gene
causes
glucocorticoid-remediable aldosteronism and human
hypertension. Nature 355:262–5
103. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon
RD 1995 A new genetic test for familial
hyperaldosteronism type I aids in the detection of curable
hypertension. Biochem Biophys Res Commun 207:565–71
104. Fardella CE, Pinto M, Mosso L, Gomez-Sanchez C, Jalil
J, Montero J 2001 Genetic study of patients with
dexamethasone-suppressible aldosteronism without the
chimeric CYP11B1/CYP11B2 gene. J Clin Endocrinol
Metab 86:4805–7
105. Gates LJ, Benjamin N, Haites NE, MacConnachie AA,
McLay JS 2001 Is random screening of value in detecting
glucocorticoid-remediable aldosteronism within a
hypertensive population? J Hum Hypertens 15:173–6
106. So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, New
MI, Stowasser M 2005 Familial hyperaldosteronism type II
is linked to the chromosome 7p22 region but also shows
predicted heterogeneity. J Hypertens 23:1477–84
93.
Conn JW, Morita R, Cohen EL, Beierwaltes WH,
McDonald WJ, Herwig KR 1972 Primary aldosteronism.
Photoscanning of tumors after administration of 131 I-19iodocholesterol. Arch Intern Med 129:417–25
107. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn
WL, Krek AL 1991 Clinical and pathological diversity of
primary aldosteronism, including a new familial variety.
Clin Exp Pharmacol Physiol 18:283–6
94.
Sarkar SD, Cohen EL, Beierwaltes WH, Ice RD, Cooper
R, Gold EN 1977 A new and superior adrenal imaging
agent, 131I-6beta-iodomethyl-19-nor-cholesterol (NP-59):
evaluation in humans. J Clin Endocrinol Metab 45:353–62
108. Stowasser M, Gordon RD 2003 Primary aldosteronism:
from genesis to genetics. Trends Endocrinol Metab
14:310–7
95.
Hogan MJ, McRae J, Schambelan M, Biglieri EG 1976
Location of aldosterone-producing adenomas with 131I-19iodocholesterol. N Engl J Med 294:410–4
109. Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin
JP, Huggard P, Gordon RD, Stratakis CA 2000 A novel
genetic locus for low renin hypertension: familial
hyperaldosteronism type II maps to chromosome 7 (7p22).
J Med Genet 37:831–5
96.
Nomura K, Kusakabe K, Maki M, Ito Y, Aiba M, Demura
H 1990 Iodomethylnorcholesterol uptake in an
aldosteronoma shown by dexamethasone-suppression
scintigraphy: relationship to adenoma size and functional
activity. J Clin Endocrinol Metab 71:825–30
110. Blumenfeld JD, Sealey JE, Schlussel Y, Vaughan ED, Jr.,
Sos TA, Atlas SA, Muller FB, Acevedo R, Ulick S,
Laragh JH 1994 Diagnosis and treatment of primary
hyperaldosteronism. Ann Intern Med 121:877–85
97.
Mansoor GA, Malchoff CD, Arici MH, Karimeddini MK,
Whalen GF 2002 Unilateral adrenal hyperplasia causing
primary aldosteronism: limitations of I-131 norcholesterol
scanning. Am J Hypertens 15:459–64
111. Harris DA, Au-Yong I, Basnyat PS, Sadler GP, Wheeler
MH 2003 Review of surgical management of aldosterone
secreting tumours of the adrenal cortex. Eur J Surg Oncol
29:467–74
98.
Biglieri EG, Schambelan M 1979 The significance of
elevated levels of plasma 18-hydroxycorticosterone in
patients with primary aldosteronism. J Clin Endocrinol
Metab 49:87–91
112. Rossi H, Kim A, Prinz RA 2002 Primary
hyperaldosteronism in the era of laparoscopic
adrenalectomy. Am Surg 68:253–6; discussion 256–7
113. Stowasser M, Klemm SA, Tunny TJ, Storie WJ,
Rutherford JC, Gordon RD 1994 Response to unilateral
adrenalectomy for aldosterone-producing adenoma: effect
of potassium levels and angiotensin responsiveness. Clin
Exp Pharmacol Physiol 21:319–22
not hyperplastic primary aldosteronism. Hypertension
5:V115–21
114. Young WF, Jr. 2003 Minireview: primary aldosteronism-changing concepts in diagnosis and treatment.
Endocrinology 144:2208–13
129. Kremer D, Beevers DG, Brown JJ, Davies DL, Ferriss
JB, Fraser R, Lever AF, Robertson JI 1973
Spironolactone and amiloride in the treatment of low renin
hyperaldosteronism and related syndromes. Clin Sci Mol
Med Suppl 45 Suppl 1:213s–8
115. Lo CY, Tam PC, Kung AW, Lam KS, Wong J 1996
Primary aldosteronism. Results of surgical treatment. Ann
Surg 224:125–30
116. Proye CA, Mulliez EA, Carnaille BM, Lecomte-Houcke
M, Decoulx M, Wemeau JL, Lefebvre J, Racadot A, Ernst
O, Huglo D, Carre A 1998 Essential hypertension: first
reason for persistent hypertension after unilateral
adrenalectomy for primary aldosteronism? Surgery
124:1128–33
117. Jacobsen NE, Campbell JB, Hobart MG 2003
Laparoscopic versus open adrenalectomy for surgical
adrenal disease. Can J Urol 10:1995–9
118. Rutherford JC, Stowasser M, Tunny TJ, Klemm SA,
Gordon RD 1996 Laparoscopic adrenalectomy. World J
Surg 20:758–60; discussion 761
119. Ishidoya S, Ito A, Sakai K, Satoh M, Chiba Y, Sato F,
Arai Y 2005 Laparoscopic partial versus total
adrenalectomy for aldosterone producing adenoma. J Urol
174:40–3
120. Ghose RP, Hall PM, Bravo EL 1999 Medical management
of aldosterone-producing adenomas. Ann Intern Med
131:105–8
122. Mattsson C, Young WF, Jr. 2006 Primary aldosteronism:
diagnostic and treatment strategies. Nat Clin Pract Nephrol
2:198–208
123. Rutherford JC, Taylor WL, Stowasser M, Gordon RD
1998 Success of surgery for primary aldosteronism judged by
residual autonomous aldosterone production. World J Surg
22:1243–5
124. Brown JJ, Davies DL, Ferriss JB, Fraser R, Haywood E,
Lever AF, Robertson JI 1972 Comparison of surgery and
prolonged spironolactone therapy in patients with
hypertension, aldosterone excess, and low plasma renin. Br
Med J 2:729–34
125. Crane MG, Harris JJ 1970 Effect of spironolactone in
hypertensive patients. Am J Med Sci 260:311–30
126. Ganguly A, Luetscher JA 1976 Spironolactone therapy in
primary aldosteronism: diagnostic and therapeutic
implications. In: Sambhi MP (ed) Systemic effects of
antihypertensive agents. Stratton, New York; pp 383–392
127. Helber A, Wambach G, Hummerich W, Bonner G,
Meurer KA, Kaufmann W 1980 Evidence for a subgroup of
essential hypertensives with non-suppressible excretion of
aldosterone during sodium loading. Klin Wochenschr
58:439–47
128. Kater CE, Biglieri EG, Schambelan M, Arteaga E 1983
Studies of impaired aldosterone response to spironolactoneinduced renin and potassium elevations in adenomatous but
131. Lim PO, Jung RT, MacDonald TM 1999 Raised
aldosterone to renin ratio predicts antihypertensive efficacy
of spironolactone: a prospective cohort follow-up study. Br
J Clin Pharmacol 48:756–60
132. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A,
DeVries C, Plouin PF, Corvol P, Menard J 1987 Efficacy
and tolerance of spironolactone in essential hypertension.
Am J Cardiol 60:820–5
133. de Gasparo M, Joss U, Ramjoue HP, Whitebread SE,
Haenni H, Schenkel L, Kraehenbuehl C, Biollaz M, Grob
J, Schmidlin J, et al. 1987 Three new epoxy-spirolactone
derivatives: characterization in vivo and in vitro. J
Pharmacol Exp Ther 240:650–6
134. Burgess ED, Lacourciere Y, Ruilope-Urioste LM, Oparil
S, Kleiman JH, Krause S, Roniker B, Maurath C 2003
Long-term safety and efficacy of the selective aldosterone
blocker eplerenone in patients with essential hypertension.
Clin Ther 25:2388–404
135. Weinberger MH, Roniker B, Krause SL, Weiss RJ 2002
Eplerenone, a selective aldosterone blocker, in mild-tomoderate hypertension. Am J Hypertens 15:709–16
136. Pitt B, Remme W, Zannad F, Neaton J, Martinez F,
Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M
2003 Eplerenone, a selective aldosterone blocker, in
patients with left ventricular dysfunction after myocardial
infarction. N Engl J Med 348:1309–21
137. Lim PO, Young WF, MacDonald TM 2001 A review of the
medical treatment of primary aldosteronism. J Hypertens
19:353–61
138. Farquharson CA, Struthers AD 2000 Spironolactone
increases nitric oxide bioactivity, improves endothelial
vasodilator dysfunction, and suppresses vascular
angiotensin I/angiotensin II conversion in patients with
chronic heart failure. Circulation 101:594–7
139. Farquharson CA, Struthers AD 2002 Increasing plasma
potassium with amiloride shortens the QT interval and
reduces ventricular extrasystoles but does not change
endothelial function or heart rate variability in chronic
heart failure. Heart 88:475–80
CASE DETECTION, DIAGNOSIS, AND TREATMENT OF PATIENTS WITH PRIMARY ALDOSTERONISM
121. Sywak M, Pasieka JL 2002 Long-term follow-up and cost
benefit of adrenalectomy in patients with primary
hyperaldosteronism. Br J Surg 89:1587–93
130. Wambach G, Helber A, Bonner G, Hummerich W,
Meurer KA, Kaufmann W 1980 [Spironolactone in
essential hypertension associated with abnormal
aldosterone regulation and in Conn’s syndrome (author's
transl)]. Dtsch Med Wochenschr 105:647–51
25
Acknowledgments
In addition to the members of the Task Force, there have been a number of people whose contribution to these
guidelines has been invaluable. First, we would like to thank Dr. Robert Vigersky, the members of the Clinical
Guidelines Subcommittee, the Clinical Affairs Core Committee, and the Council of The Endocrine Society for
their careful reading of and very useful suggestions for improving the guidelines. Second, we thank the members
of The Endocrine Society at large for their input when the draft guidelines were posted on the Society’s website;
all the responses received were considered by the authors, and many incorporated. Third, we thank the members
of our sister societies around the world for their enthusiastic involvement in reading the draft guidelines, and in
offering their support for this publication. Fourth, we thank Lisa Marlow of The Endocrine Society, who has
provided first-class administrative and logistic back-up, without which such a geographically disperse task force
would have faced considerable difficulty in operating. Last, but very much not least, the authors are indebted to
Dr. Patricia A. Stephens, medical writer, for her unfailing patience, her meticulous checking of both text and
references, and most importantly her ability to meld half a dozen disparate writing styles into a seamless whole.
THE ENDOCRINE SOCIETY’S CLINICAL GUIDELINES
Financial Disclosure of Task Force
26
John W. Funder, MD, PhD (chair)—Financial or Business/Organizational Interests: Schering-Plough, DaiichiSankyo, Pfizer, Cancer Institute of N.S.W, Speedel, Garnett Passe and Rodney Williams Memorial Foundation,
Merck, Eli Lilly, P3 Panel (Commonwealth of Australia); Significant Financial Interest or Leadership Position:
Schering-Plough, Pfizer, Daiichi-Sankyo and Cancer Institute of N.S.W. Robert M. Carey, MD—Financial or
Business/Organizational Interests: Novartis, Pfizer, Daiichi-Sankyo; Significant Financial Interest or Leadership
Position: none declared. Carlos Fardella, MD—Financial or Business/Organizational Interests: National Fund for
Scientific and Technological Development (Fondo Nacional de Desarrollo Científico y Tecnológico
[FONDECYT]); Significant Financial Interest or Leadership Position: none declared. Celso E. Gomez-Sanchez,
MD—Financial or Business/Organizational Interests: American Heart Association; Significant Financial Interest
or Leadership Position: Associate Editor for the journal Hypertension. Franco Mantero, MD, PhD—Financial or
Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: Executive
Committee of the International Society of Endocrinology. Michael Stowasser, MBBS, FRACP, PhD—Financial
or Business/Organizational Interests: none declared; Significant Financial Interest or Leadership Position: none
declared. William F. Young Jr., MSc, MD—Financial or Business/Organizational Interests: none declared;
Significant Financial Interest or Leadership Position: Mayo Clinic, Clinical Endocrinology. *Victor M. Montori,
MD—Financial or Business/Organizational Interests: KER Unit (Mayo Clinic); Significant Financial Interest or
Leadership Position: none declared.
*Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society.
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815-5817
Phone 301.941.0210; Fax 301.941.0257
[email protected]
FEIN 73-0521256
THE ENDOCRINE SOCIETY
GUIDELINE ORDER FORM
(Single reprint request for orders of 100 and less)
PRODUCTS
QTY.
PRICE (USD)
Member
SUBTOTAL
Non-Member
Androgen Therapy in Women:
An Endocrine Society Clinical Practice Guideline
$15.00
$20.00
Case Detection, Diagnosis, and Treatment of Patients with Primary
Aldosteronism: An Endocrine Society Clinical Practice Guideline
$15.00
$20.00
The Diagnosis of Cushing’s Syndrome:
An Endocrine Society Clinical Practice Guideline
$15.00
$20.00
Evaluation & Treatment of Adult Growth Hormone Deficiency:
An Endocrine Society Clinical Practice Guideline
$15.00
$20.00
Evaluation & Treatment of Hirsutism in Premenopausal Women:
An Endocrine Society Clinical Practice Guideline
$15.00
$20.00
Executive Summary
(MMTD07)—$10.00
Executive Summary
(MMTD07)—$15.00
Guideline (MTSD07)—
$10.00
Guideline (MTSD07)—
$15.00
$15.00
$20.00
Management of Thyroid Dysfunction during Pregnancy and
Postpartum: An Endocrine Society Clinical Practice Guideline
Testosterone Therapy in Adult Men with Androgen Deficiency
Syndromes: An Endocrine Society Clinical Practice Guideline
Miscellaneous
TOTAL
All prices include sales tax
PAYMENT INFORMATION:
m Check
m MasterCard
m Visa
Card Number
Expiration Date
Billing Address
Signature
m Yes
Are you a member of The Endocrine Society?
$
m No
If you are a member and you know your member ID, please provide: ___________________________________________________________
Prefix:
First Name (Given):
Middle:
Institution/Company:
Last (Surname):
Dept/Div:
Street/PO:
City:
State/Province:
Zip/Mail Code:
Telephone:
Fax:
Email:
Degree(s) that you would like listed after your name:
Professional Title:
Date of Birth:
Which of the following best describes your primary professional role?
(Please mark only one)
m
m
m
m
m
m
Administrator
Basic Researcher
Clinical Practitioner
Clinical Researcher
Industry/Corporate Professional
Nurse/Healthcare Professional
m
m
m
m
m
m
Retired
Teacher/Educator
Fellow (Clinical)
Fellow (Postdoctoral/Research)
Student
Other___________________________________
Country:
Gender:
m
Male
m
Female
Race or Ethnic Affiliation (voluntary)
m
m
m
m
m
m
m
African American, Black
Asian
Hispanic
Native American, Eskimo, Aleut
Pacific Islander
White, Caucasian
Other___________________________________
What goes into our
Clinical Guidelines
is a story worth telling
The extensive process that goes into creating The Endocrine
Society’s Clinical Guidelines not only provides validation and
assurance, but also raises the standard for the development of
guidelines everywhere.
The guidelines are developed using a multi-step process that reflects
the standards of excellence embraced by The Endocrine Society.
Endocrine Society Clinical Guidelines
Coming Soon:
•
Primary Prevention of Cardiovascular
Disease and Type 2 Diabetes in Patients
at Metabolic Risk
•
Prevention and Treatment of Pediatric
Obesity
•
Evaluation and Management of Adult
Hypoglycemic Disorders
•
Endocrine Treatment of Adolescent & Adult
Transsexuals
•
Vitamin D & Bone
•
Managing Patients Post-Bariatric Surgery
•
Continuous Glucose Monitoring
•
Congenital Adrenal Hyperplasia
•
Lipids (with an endocrine focus)
•
Pituitary Incidentaloma
Endocrine Society Clinical Guidelines Now Available:
Evaluation and Treatment of
Adult Growth Hormone Deficiency
Testosterone Therapy in Adult Men with
Androgen Deficiency Syndromes
Androgen Therapy in Women
Management of Thyroid Dysfunction during
Pregnancy and Postpartum
Evaluation and Treatment of Hirsutism in
Premenopausal Women
The Diagnosis of Cushing’s Syndrome
Case Detection, Diagnosis, and Treatment of Patients
with Primary Aldosteronism
To purchase the available guidelines visit:
www.endo-society.org/guidelines/Current-Clinical-Practice-Guidelines.cfm.
To view patient guides (companion pieces to the clinical guidelines), visit
The Hormone Foundation’s Web site at www.hormone.org/public/patientguides.cfm.
Commercial Reprint Information
For information on reprint requests of more than 101 and commercial reprints contact:
Authors: John W. Funder, Robert M. Carey, Carlos Fardella, Celso E. Gomez-Sanchez, Franco Mantero, Michael
Stowasser, William F. Young Jr., and Victor M. Montori
Affiliations: Prince Henry’s Institute of Medical Research (J.W.F.), Clayton; Australia; University of Virginia
Health System (R.M.C.), Charlottesville, Virginia; Facultad de Medicina Pontificia Universidad Católica de
Chile (C.F.), Santiago; Chile; G.V. (Sonny) Montgomery VA Medical Center (C.E.G-S.), Jackson, Mississippi;
University of Padova (F.M.), Padua; Italy; University of Queensland (M.S.), Brisbane; Australia; and Mayo Clinic
(W.F.Y., V.M.M.), Rochester, Minnesota.
Co-Sponsoring Associations: European Society of Endocrinology, European Society of Hypertension,
International Society of Endocrinology, International Society of Hypertension, The Japanese Society of
Hypertension
Disclaimer Statement: Clinical Practice Guidelines are developed to be of assistance to endocrinologists by
providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered
inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific
outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a
particular patient. Treatment decisions must be made based on the independent judgment of health care providers
and each patient's individual circumstances.
The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifically
excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be
liable for direct, indirect, special, incidental, or consequential damages related to the use of the information
contained herein.
Heather Edwards
Reprint Sales Specialist
Cadmus Professional Communications
Phone:
Fax:
Email:
410.691.6214
410.684.2789
[email protected]
Single Reprint Information
For information on reprints of 100 and fewer, complete the guideline order form and return using one of the
following methods:
Mail:
The Endocrine Society
c/o Bank of America
P.O. Box 630721
Baltimore, MD 21263-0736
Fax:
Email:
301.941.0257
Societyservices @ endo-society.org
Questions & Correspondences
The Endocrine Society
Attn: Government & Public Affairs Department
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815
Phone:
Email:
Web:
301.941.0200
govt-prof @ endo-society.org
www.endo-society.org
For more information on The Endocrine Society’s Clinical Practice Guidelines or to download the complete
version of this guideline, visit http://www.endo-society.org/guidelines/index.cfm.
First published in the Journal of Clinical Endocrinology & Metabolism, September 2008, 93(9):
3266–3281
© The Endocrine Society, 2008
PPA08
The Endocrine Society’s
CLINICAL
GUIDELINES
Case Detection, Diagnosis,
and Treatment of Patients
with Primar y Aldosteronism:
An Endocrine Society Clinical Practice Guideline
The Endocrine Society
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815
301.941.0200
www.endo-society.org